Enhanced bioavailability of polyunsaturated fatty acids

ABSTRACT

Described herein are pharmaceutical compositions providing enhanced bioavailability of polyunsaturated fatty acids and methods of manufacturing the same. In particular, described herein are pharmaceutical compositions comprising soft enteric capsules that provide enhanced bioavailability of omega-3 polyunsaturated fatty acids. The oral pharmaceutical compositions described herein are useful as nutritional supplements or for the treatment of cardiovascular-related diseases, such as hyper dyslipidemia and moderate to high triglyceride levels.

CROSS REFERENCE TO RELATED APPLICATIONS

This application claims priority to U.S. Provisional Patent ApplicationNo. 62/017,489, filed Jun. 26, 2014, which is incorporated by referenceherein in its entirety. This application also claims priority to and isa continuation in part of U.S. patent application Ser. No. 14/527,201and International Patent Application No. PCT/US2014/062892, both filedon Oct. 29, 2014, both of which are incorporated by reference herein intheir entirety. This application is related to International PatentApplication No. PCT/US2015/37558, filed on Jun. 25, 2015, which isincorporated by reference herein in its entirety.

TECHNICAL FIELD

Described herein are pharmaceutical compositions providing enhancedbioavailability of polyunsaturated fatty acids and methods ofmanufacturing the same. In particular, described herein arepharmaceutical compositions comprising soft enteric capsules thatprovide enhanced bioavailability of omega-3 polyunsaturated fatty acids.The oral pharmaceutical compositions described herein are useful asnutritional supplements or for the treatment of cardiovascular-relateddiseases, such as hyper dyslipidemia and high triglyceride levels.

BACKGROUND

Medical professionals are increasingly recognizing the positivecardiovascular health benefits of fish oil based products. The principleoral dosage form of fish oil is a soft gelatin capsules. However, amajor limitation for consumers and patient compliance for the continuedtaking of these fish oil products is the presence of disruptive andunpleasant fishy odors associated with these traditional soft gelatinfish oil capsules. In particular, taking fish oil can result in negativeside effects, including but not limited to, gastric disturbances such asfishy eructation (belching, e.g., “fishy burps”), gastrointestinaldiscomfort, bloating, nausea, diarrhea, unpleasant fishy odor, orunpleasant fishy aftertaste.

To minimize these negative side effects, consumers often will freezetheir fish oil capsules before ingestion, which is thought to possiblyhelp prevent break down of the capsule in the esophagus and stomach.Several commercial products offer enterically coated fish oil softgelatin capsules to help circumvent capsule break down in the stomach.Other products include flavors or odor masking agents such as citrus orvanilla. However, these agents do not solve the negative side effects.In addition, there are significant problems associated with traditionalenteric coated capsules.

The use and manufacture of coated enteric dosage forms are well known inthe art. Such dosage forms are described in Remington's PharmaceuticalSciences, 18^(th) ed., Mack Publishing Co., Easton, Pa. (1990). Entericdosage forms are useful for protecting the contents of the dosage formfrom the gastric conditions of the stomach and/or to protect gastrictissue from an irritant material contained in the dosage form.

Enteric-coated dosage forms are typically produced by a film coatingprocess, where a thin film layer of an acid-insoluble (enteric) polymeris applied to the surface of a pre-manufactured dosage form, such as atablet, and to a lesser extent, hard and soft capsules. The entericcoating method involves spraying an aqueous or organic solution orsuspension of one or more enteric polymers onto tumbling or movingtablets or capsules, followed by drying at elevated temperatures.Enteric dosage forms made by this coating method can suffer from variousprocess-related problems that affect the performance and/or appearanceof the coating. For example, “orange peel” surface formation, also knownas surface roughness or mottling, may result. More seriously, coatintegrity failure may occur, such as cracking or flaking off the entericpolymer coating. All coating processes present inherent problems,including possible uneven distribution of the coating ingredients, whichcan occur under multivariate coating processes. Further, enteric coatingalso results in a hazy and opaque appearance of the capsule and requiresadditional manufacturing steps.

These problems are common to all enteric dosage forms. However, theproblems faced during the coating of gelatin or polysaccharide capsulesare even more critical due to the delicate and heat sensitive nature ofthe soft, elastic, capsule shell. Both hard and soft capsules canundergo thermally induced agglomeration and distortion of the capsuleshell. Moreover, the smoothness and elasticity of the capsule surfacemakes it difficult to form an intact, adhered enteric coating, without asubcoating step to improve the surface of the capsule for coating.Finally, the enteric coatings cause the loss of the normally shiny andclear appearance of gelatin capsule shells, which is a major reason forthe popularity and acceptance of gelatin capsules.

There is an unmet need for a cost effective, clear, non-coated entericsoft gel capsule dosage forms encapsulating omega fatty acids whereinthe potential dosage form failure is greatly diminished, and where theform does not sacrifice gel mass elasticity when wet and is more stableand mechanically stronger after drying. Furthermore, there is an unmetneed for highly bioavailable formulations for omega-3 fatty acidsupplements and drugs.

SUMMARY

Described herein, are oral pharmaceutical compositions comprising omegafatty acids in soft capsule shells that have robust gastric acidresistance and provide enhanced bioavailability. Also described hereinare oral pharmaceutical compositions comprising omega fatty acids thatreduce fishy eructation (belching, e.g., “fishy burps”), unpleasantfishy odor, or unpleasant fishy aftertaste.

One embodiment described herein is an oral controlled releasepharmaceutical composition providing enhanced bioavailability comprisingan enteric soft capsule shell encapsulating a matrix fill comprising anomega-3 polyunsaturated fatty acid having enhanced bioavailability. Inone aspect described herein, the matrix fill comprises eicosapentaenoicacid (EPA). In another aspect described herein, the matrix fillcomprises about 94% EPA free fatty acid. In another aspect describedherein, the matrix fill comprises about 250 mg to about 1000 mg of EPA.In another aspect described herein, the omega-3 polyunsaturated fattyacid does not substantially contain docosahexaenoic acid (DHA). Inanother aspect described herein, upon administration to a subject, invivo absorption and bioavailability of the omega-3 polyunsaturated fattyacid is uneffected by the presence of food in the subject'sgastrointestinal tract. In another aspect described herein, thecomposition reduces the onset or ameliorates the symptoms of anygastrointestinal side effects including, but not limited to, eructation,abdominal discomfort, nausea, diarrhea, fishy aftertaste, or fishy odor.In another aspect described herein, the capsule shell and matrix fillcomposition are stable for at least 1 year at 25° C., 60% relativehumidity. In another aspect described herein, the capsule shell does notdissolve in simulated gastric fluid (pH 1.2) for at least 1 hour, andbegins dissolution in simulated intestinal fluid (pH 6.8) within about15 minutes. In another aspect described herein, upon administration to asubject the composition provides one or more of the followingpharmacokinetic parameters: (a) a mean plasma EPA T_(max) of about 5hours to about 6 hours; (b) a mean plasma EPA C_(max) of about 122 mg/Lto about 226 mg/L; (c) a mean plasma EPA AUC_(0→τ) of about 1840 h·mg/Lto about 2860 h·mg/L; (d) a mean plasma EPA AUC_(0→∞) of about 2040·mg/Lto about 3000 mg/L; (e) a mean EPA half-life (t½) of about 37 hours toabout 43 hours; or (f) a mean EPA overall elimination rate constant(k_(e1)) of about 0.019 h−1 to about 0.020 h⁻¹. In another aspectdescribed herein, upon administration to a subject the compositionprovides one or more of the following pharmacokinetic parameters: (a) amean plasma EPA T_(max) of about 6 hours under fasting/low fatconditions; (b) a mean plasma EPA C_(max) of about 122 mg/L underfasting/low fat conditions; (c) a mean plasma EPA AUC_(0→τ) of about1840 h·mg/L under fasting/low fat conditions; (d) a mean plasma EPAAUC_(0→∞) of about 2040·mg/L under fasting/low fat conditions; (e) amean EPA half-life (t½) of about 43 h under fasting/low fat conditions;or (f) a mean EPA overall elimination rate constant (k_(e1)) of about0.019 h⁻¹ under fasting/low fat conditions; or (g) a mean plasma EPAT_(max) of about 5 hours under fed/high fat conditions; (h) a meanplasma EPA C_(max) of about 226 mg/L under fed/high fat conditions; (i)a mean plasma EPA AUC_(0→τ) of about 2860 h·mg/L under fed/high fatconditions; (j) a mean plasma EPA AUC_(0→∞) of about 3000 mg/L underfed/high fat conditions; (k) a mean EPA half-life (t½) of about 37 hoursunder fed/high fat conditions; or (1) a mean EPA overall eliminationrate constant (k_(e1)) of about 0.020 h⁻¹ under fed/high fat conditions.In another aspect described herein, upon administration to a subject theEPA has a bioavailability of greater than 50% of the bioavailability ofa reference pharmaceutical composition. In another aspect describedherein, upon administration to a subject the EPA has a bioavailabilityof greater than 70% of the bioavailability of a reference pharmaceuticalcomposition under fed conditions. In another aspect described herein,upon administration to a subject the EPA has a bioavailability ofgreater than 100% of the bioavailability of a reference pharmaceuticalcomposition under fasted/low fat conditions. In another aspect describedherein, upon administration to a subject the EPA has a bioavailabilityof about 2000% of the bioavailability of a reference pharmaceuticalcomposition under fasted/low fat conditions. In another aspect describedherein, the reference pharmaceutical composition comprises EPA ethylester in a soft gel capsule. In another aspect described herein, uponadministration to a subject, the composition does not induce asubstantial increase in LDL level relative to baseline. In anotheraspect described herein, the composition is useful for treating,retarding the progression of, delaying the onset of, prophylaxis of,amelioration of, or reducing the symptoms of a cardiovascular-relateddisease, including but not limited to hyperlipidemia orhypertriglyceridemia. In another aspect described herein, thecomposition is useful for treating, retarding the progression of,delaying the onset of, prophylaxis of, amelioration of, or reducing thesymptoms a medical condition comprising: cardiovascular-relateddiseases, hyperlipidemia, hypertriglyceridemia, hypertension,hypercholesterolemia, mixed dyslipidemia, sitosterolemia,atherosclerosis, transient ischemic attack, systolic dysfunction,diastolic dysfunction, aneurysm, aortic dissection, myocardial ischemia,acute myocardial infarction (AMI), acute ST-segment elevation myocardialinfarction (STEMI), acute non-ST-segment elevation myocardial infarction(NSTEMI), ventricular arrhythmias, angina pectoris, unstable angina(UA), and stable angina (SA), myocardial infarction, congestive heartfailure, dilated congestive cardiomyopathy, hypertrophic cardiomyopathy,restrictive cardiomyopathy, cor pulmonale, arrhythmia, valvular heartdisease, endocarditis, pulmonary embolism, venous thrombosis, peripheralvascular disease, and peripheral artery disease, rheumatoid arthritis,dysmenorrhea, attention deficit-hyperactivity disorder in children,attention deficit-hyperactivity disorder in adults, Raynaud's syndrome,stroke, osteoporosis, kidney problems, bipolar disorder, psychosis,weight loss, endometrial cancer, macular degeneration, kidney damage,dyspraxia, developmental coordination disorder, psoriasis, asthma,allergies, Alzheimer's disease, atopic dermatitis, atrial fibrillation,depression, dry eye syndrome, cataracts, chronic fatigue syndrome (CFS),chronic kidney disease, Crohn's disease, prediabetes, ulcerativecolitis, salicylate intolerance, schizophrenia, systemic lupuserythematosus (SLE), or a combination thereof. In another aspectdescribed herein, the enteric soft capsule shell comprises a filmforming polymer, one or more enteric polymers, one or more plasticizers,one or more alkali neutralizing agents, one or more solvents, andoptionally an opacifier, a filler, a coloring agent, a flavoring agent,or a pharmaceutically acceptable excipient. In another aspect describedherein, the one or more film forming polymers comprises gelatin, the oneor more enteric polymers comprises acrylic and methacrylic acidcopolymers; the one or more plasticizers comprises glycerol and triethylcitrate; the one or more solvents comprises water; the alkalineutralizing agent comprises ammonium hydroxide; and the optionalopacifier comprises titanium dioxide. In another aspect describedherein, the enteric soft capsule shell comprises: about 25% to about 40%gelatin; about 9% to about 11% acrylic and methacrylic acid copolymers;about 10% to about 20% glycerol; about 1% to about 3% triethyl citrate;about 1% to about 4% ammonium hydroxide; and about 19% to about 65%water. In another aspect described herein, the enteric soft capsuleshell comprises: about 30% gelatin; about 18% glycerol; about 1%triethyl citrate; about 10% poly(methacylic acid-co-methyl methacrylate)1:1; about 1.5% ammonium hydroxide; and about 38% water. In anotheraspect described herein, an initial peroxide concentration is not morethan about 10 meq/kg and a second peroxide concentration after storagefor about 24 months at 25° C., 60% relative humidity is not more thanabout 25 meq/kg.

Another embodiment described herein is an oral pharmaceuticalcomposition comprising an enteric soft capsule comprising about 1000 mgof about 94% eicosapentaenoic acid (EPA, free fatty acid). In anotheraspect described herein, the enteric soft capsule comprising: about 25%to about 40% gelatin; about 9% to about 11% acrylic and methacrylic acidcopolymers; about 10% to about 20% glycerol; about 1% to about 3%triethyl citrate; about 1% to about 4% ammonium hydroxide; and about 19%to about 65% water. In one aspect described herein, upon administrationto a subject, the in vivo absorption and bioavailability of theeicosapentaenoic acid is uneffected by the presence of food in thesubject's gastrointestinal tract. In another aspect described herein,upon administration to a subject the composition provides one or more ofthe following pharmacokinetic parameters: (a) a mean plasma EPA T_(max)of about 5 hours to about 6 hours; (b) a mean plasma EPA C_(max) ofabout 122 mg/L to about 226 mg/L; (c) a mean plasma EPA AUC_(0→τ) ofabout 1840 h·mg/L to about 2860 h·mg/L; (d) a mean plasma EPA AUC_(0→∞)of about 2040·mg/L to about 3000 mg/L; (e) a mean EPA half-life (t½) ofabout 37 hours to about 43 hours; or (f) a mean EPA overall eliminationrate constant (k_(e1)) of about 0.019 h−1 to about 0.020 h⁻¹. In anotheraspect described herein, upon administration to a subject the EPA has abioavailability of greater than 50% of the bioavailability of areference pharmaceutical composition. In another aspect describedherein, upon administration to a subject the EPA has a bioavailabilityof greater than 70% of the bioavailability of a reference pharmaceuticalcomposition under fed conditions. In another aspect described herein,upon administration to a subject the EPA has a bioavailability ofgreater than 100% of the bioavailability of a reference pharmaceuticalcomposition under fasted/low fat conditions. In another aspect describedherein, upon administration to a subject the EPA has a bioavailabilityof about 2000% of the bioavailability of a reference pharmaceuticalcomposition under fasted/low fat conditions. In another aspect describedherein, the reference pharmaceutical composition comprises EPA ethylester in a soft gel capsule. In another aspect described herein, uponadministration to a subject, the composition does not induce asubstantial increase in LDL level relative to baseline. In anotheraspect described herein, the pharmaceutical composition exhibits a 50%in vitro dissolution rate (% dissolution per minute) at pH 6.8, of about20 minutes. In another aspect described herein, the composition isuseful for treating, retarding the progression of, delaying the onsetof, prophylaxis of, amelioration of, or reducing the symptoms of acardiovascular-related disease including, but not limited to,hyperlipidemia or hypertriglyceridemia, without substantially inducingone or more of one or more of eructation, abdominal discomfort, nausea,diarrhea, or unpleasant fishy odor. In another aspect described herein,the composition is useful for treating, retarding the progression of,delaying the onset of, prophylaxis of, amelioration of, or reducing thesymptoms of a medical condition comprising: cardiovascular-relateddiseases, hyperlipidemia, hypertriglyceridemia, hypertension,hypercholesterolemia, mixed dyslipidemia, sitosterolemia,atherosclerosis, transient ischemic attack, systolic dysfunction,diastolic dysfunction, aneurysm, aortic dissection, myocardial ischemia,acute myocardial infarction (AMI), acute ST-segment elevation myocardialinfarction (STEMI), acute non-ST-segment elevation myocardial infarction(NSTEMI), ventricular arrhythmias, angina pectoris, unstable angina(UA), and stable angina (SA), myocardial infarction, congestive heartfailure, dilated congestive cardiomyopathy, hypertrophic cardiomyopathy,restrictive cardiomyopathy, cor pulmonale, arrhythmia, valvular heartdisease, endocarditis, pulmonary embolism, venous thrombosis, peripheralvascular disease, and peripheral artery disease, rheumatoid arthritis,dysmenorrhea, attention deficit-hyperactivity disorder in children,attention deficit-hyperactivity disorder in adults, Raynaud's syndrome,stroke, osteoporosis, kidney problems, bipolar disorder, psychosis,weight loss, endometrial cancer, macular degeneration, kidney damage,dyspraxia, developmental coordination disorder, psoriasis, asthma,allergies, Alzheimer's disease, atopic dermatitis, atrial fibrillation,depression, dry eye syndrome, cataracts, chronic fatigue syndrome (CFS),chronic kidney disease, Crohn's disease, prediabetes, ulcerativecolitis, salicylate intolerance, schizophrenia, systemic lupuserythematosus (SLE), or a combination thereof, without substantiallyinducing one or more of one or more of eructation, abdominal discomfort,nausea, diarrhea, or unpleasant fishy odor. In another aspect describedherein, the composition for administration to a subject withhyperdyslipidemia or a cardiovascular-related disease comprising atherapeutically effective amount of the fatty acids described herein,wherein the subject achieves a reduction of the annualized diseaserelapse rate relative to baseline without substantially experiencing oneor more of disruptive eructation and unpleasant fishy odors andaftertaste. In another embodiment described herein, the reduction is upto 50% or greater.

Another embodiment described herein is a method for treating, retardingthe progression of, delaying the onset of, prophylaxis of, ameliorationof, or reducing the symptoms of a cardiovascular-related diseaseincluding, but not limited to, hyperlipidemia or hypertriglyceridemia,comprising the administration of a therapeutically effective amount ofEPA free fatty acid comprising any of the pharmaceutical compositionsdescribed herein.

Another embodiment described herein is a method for treating, retardingthe progression of, delaying the onset of, prophylaxis of, ameliorationof, or reducing the symptoms of a cardiovascular-related diseaseincluding, but not limited to, hyperlipidemia or hypertriglyceridemia,comprising the administration to a subject in need thereof of one ormore oral dosage forms comprising an enteric soft capsule comprisingabout 1000 mg of about 94% eicosapentaenoic acid (EPA, free fatty acid).In another aspect described herein, the administration comprises equaldoses of about 1000 mg per day to about 4000 mg per day. In anotheraspect described herein, the enteric soft capsule comprises: about 25%to about 40% gelatin; about 9% to about 11% acrylic and methacrylic acidcopolymers; about 10% to about 20% glycerol; about 1% to about 3%triethyl citrate; about 1% to about 4% ammonium hydroxide; and about 19%to about 65% water. In another aspect described herein, theadministration is sufficient to achieve a reduction of triglyceride (TG)levels of about 25% relative to baseline in the subject withoutsubstantially inducing one or more gastrointestinal side effectsincluding but not limited to eructation, abdominal discomfort, nausea,diarrhea, fishy aftertaste, or fishy odor. In another aspect describedherein, the administration does not induce a substantial increase in LDLlevel relative to baseline. In another aspect described herein, thecardiovascular-related disease comprises: hyperlipidemia,hypertriglyceridemia, hypertension, hypercholesterolemia, mixeddyslipidemia, sitosterolemia, atherosclerosis, transient ischemicattack, systolic dysfunction, diastolic dysfunction, aneurysm, aorticdissection, myocardial ischemia, acute myocardial infarction (AMI),acute ST-segment elevation myocardial infarction (STEMI), acutenon-ST-segment elevation myocardial infarction (NSTEMI), ventriculararrhythmias, angina pectoris, unstable angina (UA), and stable angina(SA), myocardial infarction, congestive heart failure, dilatedcongestive cardiomyopathy, hypertrophic cardiomyopathy, restrictivecardiomyopathy, cor pulmonale, arrhythmia, valvular heart disease,endocarditis, pulmonary embolism, venous thrombosis, peripheral vasculardisease, and peripheral artery disease, rheumatoid arthritis,dysmenorrhea, attention deficit-hyperactivity disorder in children,attention deficit-hyperactivity disorder in adults, Raynaud's syndrome,stroke, osteoporosis, kidney problems, bipolar disorder, psychosis,weight loss, endometrial cancer, macular degeneration, kidney damage,dyspraxia, developmental coordination disorder, psoriasis, asthma,allergies, Alzheimer's disease, atopic dermatitis, atrial fibrillation,depression, dry eye syndrome, cataracts, chronic fatigue syndrome (CFS),chronic kidney disease, Crohn's disease, prediabetes, ulcerativecolitis, salicylate intolerance, schizophrenia, systemic lupuserythematosus (SLE), or a combination thereof. In another aspectdescribed herein, in vivo absorption and bioavailability of theeicosapentaenoic acid is uneffected by the presence of food in thesubject's gastrointestinal tract. In another aspect described herein,the pharmaceutical composition provides one or more of the followingpharmacokinetic parameters: (a) a mean plasma EPA T_(max) of about 5hours to about 6 hours; (b) a mean plasma EPA C_(max) of about 122 mg/Lto about 226 mg/L; (c) a mean plasma EPA AUC_(0→τ) of about 1840 h·mg/Lto about 2860 h·mg/L; (d) a mean plasma EPA AUC_(0→∞) of about 2040·mg/Lto about 3000 mg/L; (e) a mean EPA half-life (t½) of about 37 hours toabout 43 hours; or (f) a mean EPA overall elimination rate constant(k_(e1)) of about 0.019 h−1 to about 0.020 h⁻¹. In another aspectdescribed herein, upon administration to the subject the EPA has abioavailability of greater than 50% of the bioavailability of areference pharmaceutical composition. In another aspect describedherein, upon administration to the subject the EPA has a bioavailabilityof greater than 70% of the bioavailability of a reference pharmaceuticalcomposition under fed conditions. In another aspect described herein,upon administration to the subject the EPA has a bioavailability ofgreater than 100% of the bioavailability of a reference pharmaceuticalcomposition under fasted/low fat conditions. In another aspect describedherein, upon administration to a subject the EPA has a bioavailabilityof about 2000% of the bioavailability of a reference pharmaceuticalcomposition under fasted/low fat conditions. In another aspect describedherein, the reference pharmaceutical composition comprises EPA ethylester in a soft gel capsule. In another aspect described herein, uponadministration to a subject, the composition does not induce asubstantial increase in LDL level relative to baseline. In anotheraspect described herein, the dosage form exhibits a 50% in vitrodissolution rate (% dissolution per minute) at pH 6.8, of about 20minutes. In another aspect described herein, the dosage from isadministered for at least about 10 days. In another aspect describedherein, LDL-C levels are reduced by at least about 5%. In another aspectdescribed herein, HDL-C levels are reduced by at least about 5%. Inanother aspect described herein, plasma concentration of arachidonicacid is reduced by at least about 5%. In another aspect describedherein, apo A-I/apo B ratio is increased by at least about 5%. Inanother aspect described herein, the dosage form further comprises atherapeutically effective amount of one or more non-steroidalanti-inflammatory drugs, statins, or cardiovascular drugs. In anotheraspect described herein, the administration is sufficient to achieve areduction of the annualized disease relapse rate relative to baselinewithout substantially experiencing one or more of disruptive eructationand unpleasant fishy odors and aftertaste. In another aspect describedherein, the reduction is up to 50% or greater.

Another embodiment described herein is a method for manufacturing anoral pharmaceutical dosage form comprising an enteric soft capsule shelland a matrix fill comprising a fatty acid composition comprising thesteps of: (i) providing a matrix fill comprising about 1000 mg of about94% eicosapentaenoic acid (EPA, free fatty acid); (ii) providing anenteric soft capsule shell comprising about 25% to about 40% gelatin;about 9% to about 11% acrylic and methacrylic acid copolymers; about 10%to about 20% glycerol; about 1% to about 3% triethyl citrate; about 1%to about 4% ammonium hydroxide; and about 19% to about 65% water; (iii)casting the enteric soft capsule shell into films using heat-controlleddrums or surfaces; and (iv) forming an enteric soft capsule dosage formcomprising the matrix fill composition using rotary die encapsulationtechnology.

Another embodiment described herein is an oral pharmaceutical dosageform produced by any of the compositions or the methods describedherein.

Another embodiment described herein is a kit for dispensing the oralpharmaceutical dosage form produced by any of the compositions or themethods described herein comprising: (a) at least one dosage formcomprising a fatty acid composition; (b) at least one moisture proofdispensing receptacle comprising blister or strip packs, an aluminumblister, a transparent or opaque polymer blister with pouch,polypropylene tubes, colored blister materials, tubes, bottles, andbottles optionally containing a child-resistant feature, optionallycomprising a desiccant, such as a molecular sieve or silica gel; andoptionally (c) an insert comprising instructions or prescribinginformation for the fatty acid composition comprised by the oralpharmaceutical composition; or (d) an non-steroidal anti-inflammatorydrug, a statin, or a cardiovascular drug. In one aspect describedherein, the kit is useful for treating a cardiovascular-related diseaseor medical condition according to any of the methods described herein.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1. Two-stage dissolution of the pharmaceutical composition shown inTable 6 (94% EPA free fatty acid in enteric soft gel capsules). Thesample was placed in simulated gastric fluid (pH 1.2) for 1 hour andthen transferred to simulated intestinal fluid (pH 6.8). The T₅₀ is 82.6minutes, which is 22.6 minutes after the transition to pH 6.8.

FIG. 2. Single-stage dissolution of six samples of the pharmaceuticalcomposition shown in Table 6 at pH 6.8.

FIG. 3. Average of single-stage dissolution of the data in FIG. 2. Thefirst point at zero is in pH 1.2 and then the capsules were transferredto pH 6.8. The T₅₀ is 22.6 minutes at pH 6.8.

FIG. 4. Single-stage dissolution of samples of the pharmaceuticalcomposition shown in Table 6 shortly after manufacturing and after 1month under accelerated stability conditions (40° C., 75% relativehumidity).

FIG. 5. Two-stage dissolution of the pharmaceutical composition shown inTable 6 after 1 month under accelerated stability conditions (40° C.,75% relative humidity). The sample was placed in simulated gastric fluid(pH 1.2) for 1 hour and then transferred to simulated intestinal fluid(pH 6.8). The T₅₀ is 79.9 minutes, which is 19.9 minutes after thetransition to pH 6.8.

FIG. 6. Mean plasma concentration (g/mL) as a function of time and afteringestion of the RLD and the Test pharmaceutical composition shown inTable 6.

DETAILED DESCRIPTION

Described herein are pharmaceutical compositions or nutritionalsupplements comprising at least one or more polyunsaturated fatty acidsencapsulated by a gastric-resistant or enteric soft capsule shell. Thedescribed pharmaceutical compositions provide surprising andunexpectedly high bioavailability of omega-3 fatty acids for thetreatment of hyper dyslipidemia and high triglyceride levels.

As used herein, the phrase “pharmaceutical composition” encompasses“nutritional compositions” or “nutritional supplements.”

As used herein, the terms “gastric-resistant” and “enteric” are usedinterchangeably and refer to the property of a substance resistantdissolution in biological, artificial, or simulated gastric fluid (pHca. 1.2), and that dissolves in biological, artificial, or simulatedintestinal fluid (pH ca. 6.8). One embodiment described herein aregastric-resistant or enteric soft capsules.

As used herein, the term “fatty acid” refers to any carboxylic acidhaving a long aliphatic chain that can be either saturated orunsaturated. The term fatty acid further encompasses any fish oildescribed herein and any saturated, polyunsaturated, monounsaturated, orany omega-3, -6, -7, or -9 fatty acid.

As used herein, the term “bioavailability” refers to the proportion ofan active pharmaceutical ingredient that enters the systemic circulationwhen introduced into the body and is able to have a physiologicaleffect.

As used herein, the term “enhanced bioavailability” refers to theincreased proportion of an active pharmaceutical ingredient that entersthe systemic circulation when introduced into the body as compared to areference's bioavailability.

As used herein, the term “absolute bioavailability” refers to thefraction of a drug or active pharmaceutical ingredient absorbed throughnon-intravenous administration (e.g., oral administration) as comparedto intravenous administration of the same drug or active pharmaceuticalingredient.

As used herein, the term “polyunsaturated fatty acid” (“PUFA”) refers toa long chain fatty acid that contains more than one double bond in thebackbone of the chain. The term encompasses esters, re-esterifiedtriglycerides, or salts thereof.

As used herein, the term “monounsaturated fatty acid” refers to a longchain fatty acid that contains only one double bond in the backbone ofthe chain. The term encompasses esters, re-esterified triglycerides, orsalts thereof.

As used herein, the term “all-natural” refers to the enteric softcapsule shell and means that the enteric soft capsule shell does notcomprise any synthetic or artificial components.

As used herein, the terms “active ingredient,” “active pharmaceuticalingredient,” or “active pharmaceutical agent” refer to an agent, activeingredient, compound, or substance, compositions, or mixtures thereof,that provide a pharmacological, often beneficial, effect. Reference to aspecific active ingredient includes, where appropriate, the activeingredient and any of its pharmaceutically acceptable free acids, freebases, salts or esters.

As used herein, the terms “dosage” or “dose” denote any form of theactive ingredient formulation that contains an amount sufficient toproduce a therapeutic effect with a single administration. The dosageform used herein is for oral administration. The preferred oral dosageforms are soft capsules or enteric soft capsules.

As used herein, the phrases “enteric soft capsule composition,” “entericsoft capsule gel mass,” “gel mass,” or “enteric soft capsule shell” areused interchangeably and have the same meaning. Typically, as usedherein, “enteric soft capsule composition” or “gel mass” refer toenteric soft capsule compositions prior to forming the enteric softcapsule and “enteric soft capsule shell” refers to the enteric capsuleshell after having been formed into an enteric soft capsule, forexample, by using rotary die encapsulation and the matrix fillsdescribed herein that have been introduced into said soft capsule shell.

As used herein, the term “pharmaceutical composition” refers acomposition comprising at least on active ingredient, nutraceutical,nutritional, or vitamin. In some embodiments described herein, apharmaceutical composition comprises a soft capsule shell having beenformed into a capsule, for example, using rotary die encapsulationcomprising one or more polyunsaturated fatty acids, optionally with oneor more vitamins, antioxidants, or other active ingredients.

The term “formulation” or “composition” as used herein refers to theactive pharmaceutical ingredient, nutraceutical, nutritional, vitamin,or drug in combination with pharmaceutically acceptable excipients. Thisincludes orally administrable formulations as well as formulationsadministrable by other means.

The term “controlled release” as used herein refers to a compositionthat does not immediately releases an active ingredient. “Controlledrelease” as used herein encompasses the terms “modified release,”“sustained release,” “extended release,” and “delayed release.”

The term “delayed release” as used herein refers to a composition thatreleases an active ingredient according to a desired profile over anextended period under physiological conditions or in an in vitro test.By “extended period” it is meant a continuous period of time of at leastabout 20 minutes, about 30 minutes, about 1 hour; about 2 hours; about 4hours; about 6 hours; about 8 hours; about 10 hours; about 12 hours;about 14 hours; about 16 hours; about 18 hours; about 20 hours; about 24hours; or even longer.

The term “modified release” as used herein refers to a composition thatreleases an active ingredient at a slower rate than does an immediaterelease formulation under physiological conditions or in an in vitrotest.

The term “sustained release” as used herein refers to a composition thatreleases an active ingredient over an extended period of time, forexample minutes, hours, or days, such that less than all the activeingredient is released initially. A sustained release rate may provide,for example, a release of a certain specified amount of a drug or activeingredient from a dosage form, over a certain period, underphysiological conditions or in an in vitro test.

The term “extended release” as used herein refers to a composition thatreleases an active ingredient over an extended period, such as of atleast about 20 minutes, about 30 minutes, about 1 hour; about 2 hours;about 4 hours; about 6 hours; about 8 hours; about 10 hours; about 12hours; about 14 hours; about 16 hours; about 18 hours; about 20 hoursabout 24 hours; or even longer; specifically over a period of at least18 hours under physiological conditions or in an in vitro assay.

The term “C_(max)” as used herein refers to the maximum observed blood(plasma, serum, or whole blood) concentration or the maximum bloodconcentration calculated or estimated from a concentration to timecurve, and is expressed in units of mg/L or ng/mL, as applicable.

The term “C_(min)” as used herein refers to the minimum observed blood(plasma, serum, or whole blood) concentration or the minimum bloodconcentration calculated or estimated from a concentration to timecurve, and is expressed in units of mg/L or ng/mL, as applicable.

The term “C_(avg)” as used herein refers to the blood (plasma, serum, orwhole blood) concentration of the drug within the dosing interval, iscalculated as AUC/dosing interval, and is expressed in units of mg/L orng/mL, as applicable.

The term “T_(max)” as used herein refers to the time afteradministration at which C_(max) occurs, and is expressed in units ofhours (h) or minutes (min), as applicable.

The term “AUC_(0→τ)” as used herein refers to area under the blood(plasma, serum, or whole blood) concentration versus time curve fromtime zero to time tau (τ) over a dosing interval at steady state, wheretau is the length of the dosing interval, and is expressed in units ofh·mg/L or h·ng/mL, as applicable. For example, the term AUC_(0→12) asused herein refers to the area under the concentration versus time curvefrom 0 to 12 hours.

The term “AUC_(0→∞)” as used herein refers to the area under the blood(plasma, serum, or whole blood) concentration versus time curve fromtime 0 hours to infinity, and is expressed in units of h·mg/L orh·ng/mL, as applicable.

The term “room temperature” as used herein refers to common ambienttemperatures ranging from about 20° C. to about 27° C.

The term “treating” refers to administering a therapy in an amount,manner, or mode effective to improve a condition, symptom, or parameterassociated with a disorder.

The term “prophylaxis” refers to preventing or reducing the progressionof a disorder, either to a statistically significant degree or to adegree detectable to one skilled in the art.

The term “substantially” as used herein means to a great or significantextent, but not completely.

The term “about” as used herein refers to any values, including bothintegers and fractional components that are within a variation of up to±10% of the value modified by the term “about.” For example, the phrase“about 50%” is equivalent to any vale ≈50±10%, e.g., 44.6%, 45%, 46%,47%, 48%, 49%, 49.5%, 50%, 50.3%, 51%, 52%, 53%, 54%, 55%, inter alia.

As used herein, “a” or “an” means one or more unless otherwisespecified.

Terms such as “include,” “including,” “contain,” “containing,” “has,” or“having,” and the like, mean “comprising.”

The term “or” can be conjunctive or disjunctive.

Suitable active pharmaceutical ingredients comprising fatty acids forthe oral pharmaceutical composition described herein comprise fish oils,egg oils, squid oils, krill oils, nut oils, seed oils; soy oils, avocadooils, seabuckthorn seed or berry oils, clary sage seed oils, algal oils,flaxseed oils, sacha ichi oils, echium oils, or hemp oils.

In one embodiment, active pharmaceutical ingredients comprising fattyacids are obtained from fish oils. Suitable fish for extracting fish oilcomprise herring, sardines, mackerel (e.g., Spanish, king, Atlantic, orPacific mackerel), salmon, halibut, tuna, swordfish, greenshell mussels,tilefish, tuna, pollock, cod, catfish, flounder, grouper, mahi mahi,orange roughy, red snapper, shark, hoki, gemfish, blue eye cod, Sydneyrock oysters, snapper, or combinations thereof. In one aspect, the fattyacids comprise polyunsaturated fatty acids (PUFAs). In one aspect, PUFAsare obtained from fish comprising salmon, herring, mackerel, anchovies,or sardines.

Other useful pharmaceutical ingredients that can be included in thepharmaceutical compositions described herein include fish oils, eggoils, squid oils, krill oils, nut oils, seed oils; soy oils, avocadooils, seabuckthorn seed or berry oils, clary sage seed oils, algal oils,flaxseed oils, sacha ichi oils, echium oils, hemp oils, polyunsaturatedfatty acids, omega-3 fatty acids, polyunsaturated omega-3 fatty acids,hexadecatrienoic acid (HTA), alpha-linolenic acid (ALA), stearidonicacid (SDA), eicosatrienoic acid (ETE), eicosatetraenoic acid (ETA),eicosapentaenoic acid (EPA, timnodonic acid), heneicosapentaenoic acid(HPA), docosapentaenoic acid (DPA), clupanodonic acid), docosahexaenoicacid (DHA, cervonic acid), tetracosapentaenoic acid, tetracosahexaenoicacid (nisinic acid), and free acids, etheyl esters, or other esters orsalts thereof. In one aspect, the pharmaceutical ingredient is a highlypurified omega-3 fatty acid, ester, or salt thereof. In one aspectdescribed herein, the active pharmaceutical ingredient comprises thepolyunsaturated omega-3 free fatty acid, eicosapentaenoic acid (EPA).

In another embodiment, the pharmaceutical composition can comprisevitamins or minerals. “Vitamins” as used herein refers to nutraceuticalsor pharmaceutical ingredients comprising organic substances that aretypically considered essential for the normal growth and activity of asubject (e.g., a human or non-human animal patient to whom thecomposition is to be administered). Non-limiting examples of vitaminsinclude, but are not limited to vitamin A (retinol), B1 (thiamine), B2(riboflavin), B complex, B6 (pyridoxine), B12 (cobalamin), C (ascorbicacid), D (cholecalciferol), E (tocopherol), F (linoleic acid), G, H(biotin), and K, and choline, folic acid, inositol, niacin, pantothenicacid, and para-aminobenzoic acid.

Vitamins can also include naturally occurring inorganic substances suchas “minerals” that are typically considered essential for the normalgrowth and activity of a subject (e.g., a human or non-human animalpatient to whom the composition is to be administered). Examples ofminerals include, but are not limited to, boron, calcium, chromium,copper, iron, magnesium, manganese, molybdenum, nickel, phosphorus,selenium, silicon, tin, vanadium, and zinc.

In one embodiment, the pharmaceutical compositions described hereincomprise fatty acid compositions comprising omega-3 fatty acids orpolyunsaturated omega-3 fatty acids comprising hexadecatrienoic acid(HTA; all-cis 7,10,13-hexadecatrienoic acid), alpha-linolenic acid (ALA;all-cis-9,12,15-octadecatrienoic acid), stearidonic acid (SDA;all-cis-6,9,12,15,-octadecatetraenoic acid), eicosatrienoic acid (ETE;all-cis-11,14,17-eicosatrienoic acid), eicosatetraenoic acid (ETA;all-cis-8,11,14,17-eicosatetraenoic acid), eicosapentaenoic acid (EPA,timnodonic acid; all-cis-5,8,11,14,17-eicosapentaenoic acid),heneicosapentaenoic acid (HPA; all-cis-6,9,12,15,18-heneicosapentaenoicacid), docosapentaenoic acid (DPA, clupanodonic acid;all-cis-7,10,13,16,19-docosapentaenoic acid), docosahexaenoic acid (DHA,cervonic acid; all-cis-4,7,10,13,16,19-docosahexaenoic acid),tetracosapentaenoic acid (all-cis-9,12,15,18,21-tetracosapentaenoicacid), tetracosahexaenoic acid (nisinic acid;all-cis-6,9,12,15,18,21-tetracosahexaenoic acid), and free acids, etheylesters, or other esters or salts thereof. In one aspect, thepharmaceutical ingredient comprises a highly purified omega-3 free fattyacid, ester, re-esterified triglyceride, or salt thereof. In one aspect,the pharmaceutical ingredient comprises a highly purified omega-3 freefatty acid.

In another embodiment, the pharmaceutical compositions described hereincomprise polyunsaturated fatty acid compositions (PUFAs) comprisingomega-6 fatty acids or polyunsaturated omega-6 fatty acids comprisinglinoleic acid (LA; all-cis-9,12-octadecadienoic acid), gamma-linolenicacid (GLA; all-cis-6,9,12-octadecatrienoic acid), calendic acid(8E,10E,12Z-octadecatrienoic acid), eicosadienoic acid(all-cis-11,14-eicosadienoic acid), dihomo-gamma linolenic acid (DGLA;all-cis-8,11,14-eicosatrienoic acid), arachidonic acid (AA;all-cis-5,8,11,14-eicosatetraenoic acid), docosadienoic acid(all-cis-13,16-docosadienoic acid), adrenic acid(all-cis-7,10,13,16-docosatetraenoic acid), docosapentaenoic acid(osbond acid; all-cis-4,7,10,13,16-docosapentaenoic acid),tetracosatetraenoic acid (all-cis-9,12,15,18-tetracosatetraenoic acid),tetracosapentaenoic acid (all-cis-6,9,12,15,18-tetracosapentaenoic acid)and free acids, etheyl esters, or other esters or salts thereof. In oneaspect, the pharmaceutical ingredient comprises a highly purifiedomega-6 fatty acid, ester, re-esterified triglyceride, or salt thereof.

In another embodiment described herein, the pharmaceutical compositioncomprises a lipid or lipophilic vehicle. Exemplary lipid or lipophilicvehicles comprise mineral oil; light mineral oil; natural oils (e.g.,vegetable, corn, canola, sunflower, soybean, olive, coconut, cocoa,peanut, almond, cottonseed, persic, sesame, squalane, castor, cod liver)hydrogenated vegetable oil; partially hydrogenated oils; beeswax;polyethoxylated beeswax; paraffin; normal waxes; medium chainmonoglycerides, diglycerides and triglycerides; higher aliphaticalcohols; higher aliphatic acids; long chain fatty acids; saturated orunsaturated fatty acids; hydrogenated fatty acids; fatty acidglycerides; polyoxyethylated oleic glycerides; monoglycerides anddiglycerides; mono-, bi- or tri-substituted glycerides; glycerolmono-oleate esters; glycerol mono-caprate; glyceryl monocaprylate;propylene glycol dicaprylate; propylene glycol monolaurate; glycerylpalmitostearate; glyceryl behenate; diethyleneglycol palmitostearate;polyethyleneglycol stearate; polyoxyethyleneglycol palmitostearate;glyceryl mono palmitostearate; cetyl palmitate; polyethyleneglycolpalmitostearate; dimethylpolysiloxane; mono- or di-glyceryl behenate;fatty alcohols associated with polyethoxylate fatty alcohols; cetylalcohol; octyl dodecanol; myristyl alcohol; isopropyl myristate,isopropyl palmitate, stearic acid, or stearyl alcohol, inter alia, orcombinations thereof.

In another embodiment described herein, the pharmaceutical compositioncomprises a solvent or solubility enhancing agent. Exemplary solvents orsolubility enhancing agents useful for the matrix fills described hereininclude Capmul® MCM, Captex® 355, Cremophor® RH 40, Croscarmellose,Crospovidone, Crospovidone CL, Crospovidone CL-F, Crospovidone CL-M,Imwitor® 742, Kollidon® CL, Kollidon® CL-F, Kollidon® CL-M, Labrafac™Lipophile WL 1349, Labrafil® M2125CS, Labrasol®, Lutrol® F 68, Maisine™35-1, mannitol, Miglyol® 812, Pearlitol® Flash, Peceol®, polyethyleneglycol 400, polyethylene glycol 600, polyethylene glycol 3350, Plurol®Oleique CC 497, Povidone K 17, Povidone K 30, propylene glycol, orcombinations thereof.

In another embodiment described herein, the pharmaceutical compositioncomprises a release regulator such as a fatty acid salt, fatty acidester, or fatty acid polyoxyethylene derivative. The release regulatorcan also be a surfactant having a hydrophilic/lipophilic balance (HLB)value between about 2 and about 40. The HLB characteristic ofsurfactants can be determined in accordance with “Physical Pharmacy:Physical Chemical Principles in the Pharmaceutical Sciences,” FourthEdition, pp. 371-373, A. Martin, Ed., Lippincott Williams & Wilkins,Philadelphia (1993), which is incorporated by reference herein for suchteachings.

In another embodiment described herein, the pharmaceutical compositioncomprises an emulsifying or solubilizing agents such as acacia,cholesterol, diethanolamine, glyceryl monostearate, lanolin alcohols,lecithin, mono- and di-glycerides, monoethanolamines, oleic acids, oleylalcohols, poloxamer, polyoxyethylene 50 stearate, polyoxyl 35 castoroil, polyoxyl 40 hydrogenated castor oil, polyoxyl 10 oleyl ether,polyoxyl 20 cetostearyl ether, polyoxyl 40 stearate, polysorbate 20,polysorbate 40, polysorbate 60, polysorbate 80, propylene glycoldiacetate, propylene glycol monostearate, sodium lauryl sulfate, sodiumstearate, sorbitan monolaurate, sorbitan monooleate, sorbitanmonopalmitate, sorbitan monostearate, stearic acid, trolamine,emulsifying wax, or combinations thereof.

In one embodiment described herein, the oral pharmaceutical compositionscomprise an enteric soft capsule comprising one or more activepharmaceutical ingredient in the matrix. As used herein, the capsule“matrix” comprises a composition that occupies the capsule lumen and isencapsulated by the capsule shell. In one embodiment described herein,the enteric soft capsule comprises a gastric resistant or enteric shelland a matrix fill of a pharmaceutical composition that is liquid,semi-solid, or solid. In one aspect, the matrix fill comprises one ormore active pharmaceutical ingredients. In another aspect, the matrixfill can be formulated to prevent interaction with the soft capsuleshell components and release the active pharmaceutical ingredient at aspecified rate. In another aspect, the matrix fill can comprisepharmaceutically acceptable vehicles, excipients, colors, or flavorings.

In one embodiment descried herein, the enteric soft capsule comprises amatrix fill comprising an active pharmaceutical ingredient comprising atleast one or more fatty acids. In one aspect, the matrix fill comprisesa pharmaceutical composition comprising one or more PUFAs.

In one embodiment, the oral pharmaceutical composition described hereincomprises a matrix fill comprising the composition of Table 1, includingall possible iterations of the specified ranges that provide 100% forthe total weight percentage.

TABLE 1 Exemplary Fatty Acid (FA) Oil Matrix Fills Component Percentweight (%) Omega-3 FAs 35-99 Omega-6 FAs ≦35 EPA 10-99 DHA 0.01-75  DPA 1-15 EPA and DHA 40-99 EPA, DHA, and DPA 40-99 Arachidonic acid ≦15Other unsaturated FAs ≦15 Saturated FAs ≦3 Antioxidants 0.01-5  Fat-soluble Vitamins 0.001-5   

In one embodiment, the pharmaceutical composition comprises acomposition of omega-3 fatty acids comprising at least about 35% to atleast about 50% by weight of all fatty acids in the pharmaceuticalcomposition including all iterations of integers within the specifiedrange. In one aspect, pharmaceutical composition comprises a compositionof omega-3 fatty acids comprising at least about 35% by weight of allfatty acids in pharmaceutical composition. In another aspect, thepharmaceutical composition comprises a composition of omega-3 fattyacids comprising at least about 40% by weight of all fatty acids in thepharmaceutical composition. In another aspect, the pharmaceuticalcomposition comprises a composition of omega-3 fatty acids comprising atleast about 45% by weight of all fatty acids in the pharmaceuticalcomposition. In another aspect, the pharmaceutical composition comprisesa composition of omega-3 fatty acids comprising at least about 50% byweight of all fatty acids in the pharmaceutical composition. In anotheraspect, the omega-3 fatty acids may be a fatty acid, ester,re-esterified triglyceride, or salt thereof.

In another embodiment, the pharmaceutical composition comprises acomposition of omega-3 fatty acids comprising of at least about 50% toat least about 85% by weight of all fatty acids in the pharmaceuticalcomposition including all iterations of integers within the specifiedrange. In one aspect, the pharmaceutical composition comprises acomposition of omega-3 fatty acids comprising at least about 50% byweight of all fatty acids in the pharmaceutical composition. In anotheraspect, the pharmaceutical composition comprises a composition ofomega-3 fatty acids comprising at least about 60% by weight of all fattyacids in the pharmaceutical composition. In another aspect, thepharmaceutical composition comprises a composition of omega-3 fattyacids comprising at least about 70% by weight of all fatty acids in thepharmaceutical composition. In another aspect, the pharmaceuticalcomposition comprises a composition of omega-3 fatty acids comprising atleast about 80% by weight of all fatty acids in the pharmaceuticalcomposition. In another aspect, the omega-3 fatty acids may be a fattyacid, ester, re-esterified triglyceride, or salt thereof.

In another embodiment, the pharmaceutical composition comprises acomposition of omega-3 fatty acids comprising of at least about 85% toat least about 99% by weight of all fatty acids in the pharmaceuticalcomposition including all iterations of integers within the specifiedrange. In one aspect, the pharmaceutical composition comprises acomposition of omega-3 fatty acids comprising at least about 85% byweight of all fatty acids in the pharmaceutical composition. In anotheraspect, the pharmaceutical composition comprises a composition ofomega-3 fatty acids comprising at least about 90% by weight of all fattyacids in the pharmaceutical composition. In another aspect, thepharmaceutical composition comprises a composition of omega-3 fattyacids comprising at least about 95% by weight of all fatty acids in thepharmaceutical composition. In another aspect, the pharmaceuticalcomposition comprises a composition of omega-3 fatty acids comprising atleast about 99% by weight of all fatty acids in the pharmaceuticalcomposition. In another aspect, the omega-3 fatty acids may be a fattyacid, ester, re-esterified triglyceride, or salt thereof.

In one embodiment, the pharmaceutical composition comprises omega-3fatty acids (e.g., EPA, DHA, or DPA, or a combination thereof) describedherein in an amount of about 50 mg to about 5000 mg, about 75 mg toabout 2500 mg, or about 100 mg to about 1000 mg including all iterationsof integers within the specified ranges. In another embodiment, thepharmaceutical composition comprises the omega-3 (e.g., EPA, DHA, orDPA, or a combination thereof) fatty acids described herein in an amountof, for example, about 50 mg, about 75 mg, about 100 mg, about 125 mg,about 150 mg, about 175 mg, about 200 mg, about 225 mg, about 250 mg,about 275 mg, about 300 mg, about 325 mg, about 350 mg, about 375 mg,about 400 mg, about 425 mg, about 450 mg, about 475 mg, about 500 mg,about 525 mg, about 550 mg, about 575 mg, about 600 mg, about 625 mg,about 650 mg, about 675 mg, about 700 mg, about 725 mg, about 750 mg,about 775 mg, about 800 mg, about 825 mg, about 850 mg, about 875 mg,about 900 mg, about 925 mg, about 950 mg, about 975 mg, about 1000 mg,about 1025 mg, about 1050 mg, about 1075 mg, about 1100 mg, about 1125mg, about 1150 mg, about 1175 mg, about 1200 mg, about 1225 mg, about1250 mg, about 1275 mg, about 1300 mg, about 1325 mg, about 1350 mg,about 1375 mg, about 1400 mg, about 1425 mg, about 1450 mg, about 1475mg, about 1500 mg, about 1525 mg, about 1550 mg, about 1575 mg, about1600 mg, about 1625 mg, about 1650 mg, about 1675 mg, about 1700 mg,about 1725 mg, about 1750 mg, about 1775 mg, about 1800 mg, about 1825mg, about 1850 mg, about 1875 mg, about 1900 mg, about 1925 mg, about1950 mg, about 1975 mg, about 2000 mg, about 2025 mg, about 2050 mg,about 2075 mg, about 2100 mg, about 2125 mg, about 2150 mg, about 2175mg, about 2200 mg, about 2225 mg, about 2250 mg, about 2275 mg, about2300 mg, about 2325 mg, about 2350 mg, about 2375 mg, about 2400 mg,about 2425 mg, about 2450 mg, about 2475 mg, or about 2500 mg about 2550mg, about 2575 mg, about 2600 mg, about 2625 mg, about 2650 mg, about2675 mg, about 2700 mg, about 2725 mg, about 2750 mg, about 2775 mg,about 2800 mg, about 2825 mg, about 2850 mg, about 2875 mg, about 2900mg, about 2925 mg, about 3000 mg, about 3025 mg, about 3050 mg, about3075 mg, about 3100 mg, about 3125 mg, about 3150 mg, about 3175 mg,about 3200 mg, about 3225 mg, about 3250 mg, about 3275 mg, about 3300mg, about 3325 mg, about 3350 mg, about 3375 mg, about 3400 mg, about3425 mg, about 3450 mg, about 3475 mg, about 3500 mg, about 3525 mg,about 3550 mg, about 3600 mg, about 3625 mg, about 3650 mg, about 3675mg, about 3700 mg, about 3725 mg, about 3750 mg, about 3775 mg, about3800 mg, about 3825 mg, about 3850 mg, about 3875 mg, about 4000 mg,about 4025 mg, about 4050 mg, about 4075 mg, about 4100 mg, 4125 mg,about 4150 mg, about 4175 mg, about 4200 mg, about 4225 mg, about 4250mg, about 4275 mg, about 4300 mg, about 4325 mg, about 4350 mg, about4375 mg, about 4400 mg, about 4425 mg, about 4450 mg, about 4475 mg,about 4500 mg, about 4525 mg, about 4550 mg, about 4600 mg, about 4625mg, about 4650 mg, about 4675 mg, about 4700 mg, about 4725 mg, about4750 mg, about 4775 mg, about 4800 mg, about 4825 mg, about 4850 mg,about 4875 mg, or about 5000 mg. In another aspect, the omega-3 fattyacids may be a free fatty acid, ester, re-esterified triglyceride, orsalt thereof.

In one embodiment, the pharmaceutical composition comprises omega-6fatty acids in an amount not more than about 20% to not more than about1% by weight of all fatty acids in the pharmaceutical compositionincluding all iterations of integers within the specified range. In oneembodiment, the pharmaceutical composition comprises omega-6 fatty acidsin an amount not more than about 15% by weight of all fatty acids in thepharmaceutical composition. In one aspect, the pharmaceuticalcomposition comprises omega-6 fatty acids in an amount not more thanabout 10% by weight of all fatty acids in the pharmaceuticalcomposition. In one aspect, the pharmaceutical composition comprisesomega-6 fatty acids in an amount not more than about 7% by weight of allfatty acids in the pharmaceutical composition. In one aspect, thepharmaceutical composition comprises omega-6 fatty acids in an amountnot more than about 3% by weight of all fatty acids in thepharmaceutical composition. In one aspect, the pharmaceuticalcomposition comprises omega-6 fatty acids in an amount not more thanabout 1% by weight of all fatty acids in the pharmaceutical composition.In one aspect, the pharmaceutical composition comprises essentially noomega-6 fatty acids.

In one embodiment, the pharmaceutical composition comprises EPA. Inanother embodiment, the pharmaceutical composition comprises EPA in anamount of about 10% to about 70% by weight of all fatty acids in thepharmaceutical composition including all iterations of integers withinthe specified range. In another aspect, the pharmaceutical compositioncomprises EPA in an amount of about 20% by weight of all fatty acids inthe pharmaceutical composition. In another aspect, the pharmaceuticalcomposition comprises EPA in an amount of about 25% by weight of allfatty acids in the pharmaceutical composition. In another aspect, thepharmaceutical composition comprises EPA in an amount of about 30% byweight of all fatty acids in the pharmaceutical composition. In anotheraspect, the pharmaceutical composition comprises EPA in an amount ofabout 35% by weight of all fatty acids in the pharmaceuticalcomposition. In another aspect, the pharmaceutical composition comprisesEPA in an amount of about 40% by weight of all fatty acids in thepharmaceutical composition. In another aspect, the pharmaceuticalcomposition comprises EPA in an amount of about 45% by weight of allfatty acids in the pharmaceutical composition. In another aspect, thepharmaceutical composition comprises EPA in an amount of about 50% byweight of all fatty acids in the pharmaceutical composition. In anotheraspect, the pharmaceutical composition comprises EPA in an amount ofabout 55% by weight of all fatty acids in the pharmaceuticalcomposition. In another aspect, the pharmaceutical composition comprisesEPA in an amount of about 60% by weight of all fatty acids in thepharmaceutical composition. In another aspect, the pharmaceuticalcomposition comprises EPA in an amount of about 65% by weight of allfatty acids in the pharmaceutical composition. In another aspect, thepharmaceutical composition comprises EPA in an amount of about 70% byweight of all fatty acids in the pharmaceutical composition. In anotheraspect, the pharmaceutical composition comprises EPA in an amount ofabout 75% by weight of all fatty acids in the pharmaceuticalcomposition. In another aspect, the pharmaceutical composition comprisesEPA in an amount of about 80% by weight of all fatty acids in thepharmaceutical composition. In another aspect, the pharmaceuticalcomposition comprises EPA in an amount of about 85% by weight of allfatty acids in the pharmaceutical composition. In another aspect, thepharmaceutical composition comprises EPA in an amount of about 90% byweight of all fatty acids in the pharmaceutical composition. In anotheraspect, the pharmaceutical composition comprises EPA in an amount ofabout 95% by weight of all fatty acids in the pharmaceuticalcomposition. In another aspect, the EPA may be a free fatty acid, ester,re-esterified triglyceride, or salt thereof.

In another embodiment, the pharmaceutical composition comprises EPA inan amount of about 70% to about 99% by weight of all fatty acids in thepharmaceutical composition including all iterations of integers withinthe specified range. In one aspect, the pharmaceutical compositioncomprises EPA in an amount of about 75% by weight of all fatty acids inthe pharmaceutical composition. In another aspect, the pharmaceuticalcomposition comprises EPA in an amount of about 80% by weight of allfatty acids in the pharmaceutical composition. In another aspect, thepharmaceutical composition comprises EPA in an amount of about 85% byweight of all fatty acids in the pharmaceutical composition. In anotheraspect, the pharmaceutical composition comprises EPA in an amount ofabout 90% by weight of all fatty acids in the pharmaceuticalcomposition. In another aspect, the pharmaceutical composition comprisesEPA in an amount of about 95% by weight of all fatty acids in thepharmaceutical composition. In another aspect, the pharmaceuticalcomposition comprises EPA in an amount of about 99% by weight of allfatty acids in the pharmaceutical composition. In another aspect, theEPA may be a free fatty acid, ester, re-esterified triglyceride, or saltthereof.

In one embodiment, the pharmaceutical composition comprises EPA withsubstantially no DHA (e.g., less than about 5% DHA). In one aspect, theEPA may be a free fatty acid, ester, re-esterified triglyceride, or saltthereof.

In one embodiment, the pharmaceutical composition comprises DHA. Inanother embodiment, the pharmaceutical composition comprises DHA in anamount of about 10% to about 75% by weight of all fatty acids in thepharmaceutical composition including all iterations of integers withinthe specified range. In another embodiment, the pharmaceuticalcomposition comprises DHA in an amount of about 10% to about 50% byweight of all fatty acids in the pharmaceutical composition includingall iterations of integers within the specified range. In one aspect,the pharmaceutical composition comprises DHA in an amount of about 10%by weight of all fatty acids in the pharmaceutical composition. Inanother aspect, the pharmaceutical composition comprises DHA in anamount of about 15% by weight of all fatty acids in the pharmaceuticalcomposition. In another aspect, the pharmaceutical composition comprisesDHA in an amount of about 20% by weight of all fatty acids in thepharmaceutical composition. In another aspect, the pharmaceuticalcomposition comprises DHA in an amount of about 25% by weight of allfatty acids in the pharmaceutical composition. In another aspect, thepharmaceutical composition comprises DHA in an amount of about 30% byweight of all fatty acids in the pharmaceutical composition. In anotheraspect, the pharmaceutical composition comprises DHA in an amount ofabout 35% by weight of all fatty acids in the pharmaceuticalcomposition. In another aspect, the pharmaceutical composition comprisesDHA in an amount of about 40% by weight of all fatty acids in thepharmaceutical composition. In another aspect, the pharmaceuticalcomposition comprises DHA in an amount of about 45% by weight of allfatty acids in the pharmaceutical composition. In another aspect, thepharmaceutical composition comprises DHA in an amount of about 55% byweight of all fatty acids in the pharmaceutical composition. In anotheraspect, the pharmaceutical composition comprises DHA in an amount ofabout 60% by weight of all fatty acids in the pharmaceuticalcomposition. In another aspect, the pharmaceutical composition comprisesDHA in an amount of about 65% by weight of all fatty acids in thepharmaceutical composition. In another aspect, the pharmaceuticalcomposition comprises DHA in an amount of about 70% by weight of allfatty acids in the pharmaceutical composition. In another aspect, thepharmaceutical composition comprises DHA in an amount of about 76% byweight of all fatty acids in the pharmaceutical composition. In anotheraspect, the DHA may be a free fatty acid, ester, re-esterifiedtriglyceride, or salt thereof.

In one embodiment, the pharmaceutical composition comprises DPA. Inanother embodiment, the pharmaceutical composition comprises DPA in anamount of about 1% to about 15% by weight of all fatty acids in thepharmaceutical composition including all iterations of integers withinthe specified range. In one aspect, the pharmaceutical compositioncomprises DPA in an amount of about 1% by weight of all fatty acids inthe pharmaceutical composition. In another aspect, the pharmaceuticalcomposition comprises DPA in an amount of about 3% by weight of allfatty acids in the pharmaceutical composition. In another aspect, thepharmaceutical composition comprises DPA in an amount of about 5% byweight of all fatty acids in the pharmaceutical composition. In anotheraspect, the pharmaceutical composition comprises DPA in an amount ofabout 7% by weight of all fatty acids in the pharmaceutical composition.In another aspect, the pharmaceutical composition comprises DPA in anamount of about 10% by weight of all fatty acids in the pharmaceuticalcomposition. In another aspect, the pharmaceutical composition comprisesDPA in an amount of about 13% by weight of all fatty acids in thepharmaceutical composition. In another aspect, the DPA may be a freefatty acid, ester, re-esterified triglyceride, or salt thereof.

In one embodiment, the pharmaceutical composition comprises EPA and DHA.In another embodiment, the pharmaceutical composition comprises EPA andDHA in an amount of about 45% to about 99% by weight of all fatty acidsin the pharmaceutical composition including all iterations of integerswithin the specified range. In another embodiment, the pharmaceuticalcomposition comprises EPA and DHA in an amount of about 60% to about 99%by weight of all fatty acids in the pharmaceutical composition includingall iterations of integers within the specified range. In one aspect,the pharmaceutical composition comprises EPA and DHA in an amount ofabout 60% by weight of all fatty acids in the pharmaceuticalcomposition. In one aspect, the pharmaceutical composition comprises EPAand DHA in an amount of about 75% by weight of all fatty acids in thepharmaceutical composition. In another aspect, the pharmaceuticalcomposition comprises EPA and DHA in an amount of about 85% by weight ofall fatty acids in the pharmaceutical composition. In another aspect,the pharmaceutical composition comprises EPA and DHA in an amount ofabout 90% by weight of all fatty acids in the pharmaceuticalcomposition. In another aspect, the pharmaceutical composition comprisesEPA and DHA in an amount of about 95% by weight of all fatty acids inthe pharmaceutical composition. In another aspect, the pharmaceuticalcomposition comprises EPA and DHA in an amount of about 99% by weight ofall fatty acids in the pharmaceutical composition. In another aspect,the EPA and DHA may be a free fatty acid, ester, re-esterifiedtriglyceride, or salt thereof.

In one embodiment, the pharmaceutical composition comprises EPA, DHA,and DPA. In another embodiment, the pharmaceutical composition comprisesEPA, DHA, and DPA in an amount of about 60% to about 99% by weight ofall fatty acids in the pharmaceutical composition including alliterations of integers within the specified range. In anotherembodiment, the pharmaceutical composition comprises EPA, DHA, and DPAin an amount of about 85% to about 99% by weight of all fatty acids inthe pharmaceutical composition including all iterations of integerswithin the specified range. In one aspect, the pharmaceuticalcomposition comprises EPA, DHA, and DPA in an amount of about 85% byweight of all fatty acids in the pharmaceutical composition. In anotheraspect, the pharmaceutical composition comprises EPA, DHA, and DPA in anamount of about 90% by weight of all fatty acids in the pharmaceuticalcomposition. In another aspect, the pharmaceutical composition comprisesEPA, DHA, and DPA in an amount of about 95% by weight of all fatty acidsin the pharmaceutical composition. In another aspect, the pharmaceuticalcomposition comprises EPA, DHA, and DPA in an amount of about 99% byweight of all fatty acids in the pharmaceutical composition. In anotheraspect, the EPA, DHA, and DPA may be a free fatty acid, ester,re-esterified triglyceride, or salt thereof.

In one embodiment the pharmaceutical composition comprises a mixture ofEPA and DHA with one or more fat soluble vitamins. In one aspect, EPAcomprises about 10% to about 70% by weight of the pharmaceuticalcomposition, including each integer within the specified range. Inanother aspect, DHA comprises about 10% to about 70% by weight of thepharmaceutical composition, including each integer within the specifiedrange. In another aspect, at least another fat soluble vitamin comprisesabout 0.005% to about 5% by weight of the pharmaceutical composition,including each integer within the specified range. In another aspect thepharmaceutical composition comprises about 50% EPA and about 20% DHA,and at least another fat soluble vitamin. In another aspect, thepharmaceutical composition comprises at least about 60% EPA and at leastabout 25% DHA, and at least another fat soluble vitamin. In anotheraspect, the composition comprises at least about 45% EPA and at leastabout 20% DHA, and at least another fat soluble vitamin. In anotheraspect, the composition comprises at least about 46% EPA, at least about18% DHA, and at least another fat soluble vitamin. In another aspect,the composition comprises at least about 30% EPA, at least about 20%DHA, and at least another fat soluble vitamin. In another aspect, amixture of EPA and DHA comprising at least about 45% EPA and at leastabout 18% DHA can be combined in a 99.9:0.1 ratio with cholecalciferol(Vitamin D3) to form a pharmaceutical or nutritional composition; otherfat soluble vitamins described herein and known in the art can be addedat similar weight percentages. In another aspect, the EPA and DHA may bea free fatty acid, ester, re-esterified triglyceride, or salt thereof.

In one embodiment, the ratio of EPA to DHA in the pharmaceuticalcomposition is about 1:3 to about 9:1, including all iterations ofratios within the specified range. In one aspect, the ratio of EPA toDHA in the pharmaceutical composition is about 1:3. In another aspect,the ratio of EPA to DHA in the pharmaceutical composition is about 1:2.In another aspect, the ratio of EPA to DHA in the pharmaceuticalcomposition is about 1:1. In another aspect, the ratio of EPA to DHA inthe pharmaceutical composition is about 2:1. In another aspect, theratio of EPA to DHA in the pharmaceutical composition is about 3:1. Inanother aspect, the ratio of EPA to DHA in the pharmaceuticalcomposition is about 4:1. In another aspect, the ratio of EPA to DHA inthe pharmaceutical composition is about 5:1. In another aspect, theratio of EPA to DHA in the pharmaceutical composition is about 6:1. Inanother aspect, the ratio of EPA to DHA in the pharmaceuticalcomposition is about 7:1. In another aspect, the ratio of EPA to DHA inthe pharmaceutical composition is about 8:1. In another aspect, theratio of EPA to DHA in the pharmaceutical composition is about 9:1. Inanother aspect, the ratio of EPA to DHA in the pharmaceuticalcomposition is about 9.5:1.

In another embodiment, the pharmaceutical composition comprises lessthan about 30%, less than about 20%, less than about 10%, less thanabout 9%, less than about 8%, less than about 7%, less than about 6%,less than about 5%, less than about 4%, less than about 3%, less thanabout 2%, less than about 1%, less than about 0.5% or less than about0.25%, by weight of the total composition or by weight of the totalfatty acid content, of any unsaturated fatty acid other than EPA, DHA,or DPA. Illustrative examples of any unsaturated fatty acid other thanEPA, DHA, or DPA comprise hexadecatrienoic acid (HTA; all-cis7,10,13-hexadecatrienoic acid), alpha-linolenic acid (ALA;all-cis-9,12,15-octadecatrienoic acid), stearidonic acid (SDA;all-cis-6,9,12,15,-octadecatetraenoic acid), eicosatrienoic acid (ETE;all-cis-11,14,17-eicosatrienoic acid), eicosatetraenoic acid (ETA;all-cis-8,11,14,17-eicosatetraenoic acid), heneicosapentaenoic acid(HPA; all-cis-6,9,12,15,18-heneicosapentaenoic acid),tetracosapentaenoic acid (all-cis-9,12,15,18,21-tetracosapentaenoicacid), tetracosahexaenoic acid (nisinic acid;all-cis-6,9,12,15,18,21-tetracosahexaenoic acid), linoleic acid (LA;all-cis-9,12-octadecadienoic acid), gamma-linolenic acid (GLA;all-cis-6,9,12-octadecatrienoic acid), calendic acid(8E,10E,12Z-octadecatrienoic acid), eicosadienoic acid(all-cis-11,14-eicosadienoic acid), dihomo-gamma linolenic acid (DGLA;all-cis-8,11,14-eicosatrienoic acid), arachidonic acid (AA;all-cis-5,8,11,14-eicosatetraenoic acid), docosadienoic acid(all-cis-13,16-docosadienoic acid), Adrenic acid(all-cis-7,10,13,16-docosatetraenoic acid), docosapentaenoic acid(osbond acid; all-cis-4,7,10,13,16-docosapentaenoic acid),tetracosatetraenoic acid (all-cis-9,12,15,18-tetracosatetraenoic acid),tetracosapentaenoic acid (all-cis-6,9,12,15,18-tetracosapentaenoic acid)and free acids, etheyl esters, or other esters or salts thereof.

In one embodiment, the pharmaceutical composition comprises about 250 mgto about 5000 mg of highly pure EPA ethyl ester (e.g., at least about95% EPA). In another embodiment, the pharmaceutical compositioncomprises about 250 mg to about 2500 mg of highly pure EPA ethyl ester(e.g., at least about 95% EPA). In one aspect, the pharmaceuticalcomposition comprises about 250 mg of highly pure EPA ethyl ester (e.g.,at least about 95% EPA). In another aspect, the pharmaceuticalcomposition comprises about 500 mg of highly pure EPA ethyl ester (e.g.,at least about 95% EPA). In another aspect, the pharmaceuticalcomposition comprises about 1000 mg of highly pure EPA ethyl ester(e.g., at least about 95% EPA). In another aspect, the pharmaceuticalcomposition comprises about 2000 mg of highly pure EPA ethyl ester(e.g., at least about 95% EPA). In another aspect, the pharmaceuticalcomposition comprises about 3000 mg of highly pure EPA ethyl ester(e.g., at least about 95% EPA). In another aspect, the pharmaceuticalcomposition comprises about 4000 mg of highly pure EPA ethyl ester(e.g., at least about 95% EPA). In another aspect, the pharmaceuticalcomposition comprises about 5000 mg of highly pure EPA ethyl ester(e.g., at least about 95% EPA). See U.S. Patent Application PublicationNo. US 2010/0278879, which is incorporated by reference herein for itsspecific teachings of pure EPA ethyl esters.

In one embodiment, the pharmaceutical composition comprises at leastabout 250 mg to about 5000 mg of EPA, DHA, and DPA in an amount of about50% to about 60% EPA, 15% to about 25% DHA, and about 1% to about 8%DPA. In another embodiment, the pharmaceutical composition comprises atleast about 250 mg to about 2500 mg of EPA, DHA, and DPA in an amount ofabout 50% to about 60% EPA, 15% to about 25% DHA, and about 1% to about8% DPA. In one aspect, the pharmaceutical composition comprises at leastabout 250 mg of EPA, DHA, and DPA in an amount of about 50% to about 60%EPA, 15% to about 25% DHA, and about 1% to about 8% DPA. In anotheraspect, the pharmaceutical composition comprises at least about 500 mgof EPA, DHA, and DPA in an amount of about 50% to about 60% EPA, 15% toabout 25% DHA, and about 1% to about 8% DPA. In another aspect, thepharmaceutical composition comprises at least about 1000 mg of EPA, DHA,and DPA in an amount of about 50% to about 60% EPA, 15% to about 25%DHA, and about 1% to about 8% DPA. In another aspect, the pharmaceuticalcomposition comprises at least about 2000 mg of EPA, DHA, and DPA in anamount of about 50% to about 60% EPA, 15% to about 25% DHA, and about 1%to about 8% DPA. In another aspect, the pharmaceutical compositioncomprises at least about 3000 mg of EPA, DHA, and DPA in an amount ofabout 50% to about 60% EPA, 15% to about 25% DHA, and about 1% to about8% DPA. In another aspect, the pharmaceutical composition comprises atleast about 4000 mg of EPA, DHA, and DPA in an amount of about 50% toabout 60% EPA, 15% to about 25% DHA, and about 1% to about 8% DPA. Inanother aspect, the pharmaceutical composition comprises at least about5000 mg of EPA, DHA, and DPA in an amount of about 50% to about 60% EPA,15% to about 25% DHA, and about 1% to about 8% DPA. In another aspect,EPA, DHA, and DPA are free fatty acids. See U.S. Patent ApplicationPublication No. US 2013/0177643, which is incorporated by referenceherein for its specific teachings of DPA, EPA, and DHA compositions

In one embodiment, the pharmaceutical composition comprises about 250 mgto about 5000 mg of EPA and DHA in an amount of about 47% EPA and 38%DHA.

In another embodiment, the pharmaceutical composition comprises about250 mg to about 2500 mg of EPA and DHA in an amount of about 47% EPA and38% DHA. In one aspect, the pharmaceutical composition comprises about250 mg of EPA and DHA in an amount of about 47% EPA and 38% DHA. In oneaspect, the pharmaceutical composition comprises about 500 mg of EPA andDHA in an amount of about 47% EPA and 38% DHA. In one aspect, thepharmaceutical composition comprises about 1000 mg of EPA and DHA in anamount of about 47% EPA and 38% DHA. In one aspect, the pharmaceuticalcomposition comprises about 2000 mg of EPA and DHA in an amount of about47% EPA and 38% DHA. In one aspect, the pharmaceutical compositioncomprises about 3000 mg of EPA and DHA in an amount of about 47% EPA and38% DHA. In one aspect, the pharmaceutical composition comprises about4000 mg of EPA and DHA in an amount of about 47% EPA and 38% DHA. In oneaspect, the pharmaceutical composition comprises about 5000 mg of EPAand DHA in an amount of about 47% EPA and 38% DHA. In another aspect,the EPA and DHA may be a free fatty acid, ester, re-esterifiedtriglyceride, or salt thereof. See U.S. Pat. No. 5,656,667 isincorporated by reference herein for its specific teachings of EPA andDHA compositions.

In one embodiment, the pharmaceutical composition comprises about 410 mgof the fish oil described herein. In one aspect, the pharmaceuticalcomposition comprises about 250 mg of omega-3 fatty acids. In anotheraspect, the pharmaceutical composition comprises about 250 mg of EPA andDHA. In another aspect, the pharmaceutical composition comprises about180 mg of EPA and about 70 mg of DHA (i.e., about 44% EPA and about 17%DHA). In another aspect, the EPA is EPA ethyl ester. In another aspect,the DHA is DHA ethyl ester. In another aspect, the pharmaceuticalcomposition comprises one or more antioxidants or fat-soluble vitamins.

In one embodiment, the pharmaceutical composition comprises about 820 mgof the fish oil described herein. In one aspect, the pharmaceuticalcomposition comprises about 500 mg of omega-3 fatty acids. In oneaspect, the pharmaceutical composition comprises about 500 mg of EPA andDHA. In another aspect, the pharmaceutical composition comprises about360 mg of EPA and 140 mg of DHA (i.e., about 44% EPA and about 17% DHA).In another aspect, the EPA is EPA ethyl ester. In another aspect, theDHA is DHA ethyl ester. In another aspect, the pharmaceuticalcomposition comprises one or more antioxidants or fat-soluble vitamins.

In one embodiment, the pharmaceutical composition comprises about 600 mgof the fish oil described herein. In one aspect, the pharmaceuticalcomposition comprises about 300 mg of omega-3 fatty acids. In oneaspect, the pharmaceutical composition comprises about 270 mg of EPA andDHA. In another aspect, the pharmaceutical composition comprises about160 mg of EPA and 110 mg of DHA (i.e., about 27% EPA and about 18% DHA).In another aspect, the EPA is EPA ethyl ester. In another aspect, theDHA is DHA ethyl ester. In another aspect, the pharmaceuticalcomposition comprises one or more antioxidants or fat-soluble vitamins.

In one embodiment, the pharmaceutical composition comprises about 1200mg of the fish oil described herein. In one aspect, the pharmaceuticalcomposition comprises about 600 mg of Omega-3 fatty acids. In oneaspect, the pharmaceutical composition comprises about 540 mg of EPA andDHA. In another aspect, the pharmaceutical composition comprises about325 mg of EPA and 215 mg of DHA (i.e., about 27% EPA and about 18% DHA).In another aspect, the EPA is EPA ethyl ester. In another aspect, theDHA is DHA ethyl ester. In another aspect, the pharmaceuticalcomposition comprises one or more antioxidants or fat-soluble vitamins.

In one embodiment, the pharmaceutical composition comprises about 1400mg of the fish oil described herein. In one aspect, the pharmaceuticalcomposition comprises about 900 mg of omega-3 fatty acids. In oneaspect, the pharmaceutical composition comprises about 650 mg of EPA andDHA. In another aspect, the pharmaceutical composition comprises about647 mg of EPA and 253 mg of DHA (i.e., about 46% EPA and about 18% DHA).In another aspect, the EPA is EPA ethyl ester. In another aspect, theDHA is DHA ethyl ester. In another aspect, the pharmaceuticalcomposition comprises one or more antioxidants or fat-soluble vitamins.

In one embodiment, one or more antioxidants can be present in thepharmaceutical compositions described herein. Suitable antioxidantscomprise tocopherols (e.g., alpha tocopherol, beta tocopherol, gammatocopherol, or delta tocopherol), butylated hydroxytoluene (BHT),butylated hydroxyanisole (BHA), lecithin, citric acid, ascorbic acid,phenolic diterpenes (e.g., carnosic acid, carnosol, rosmanol,epirosmanol, isorosmanol, or methyl carnosate), rosmarinic acid,eugenol, eugenyl acetate, clove bud extract, methanolic extract, teacatechins (e.g., epigallocatechin gallate, epicatechin gallate,epigallocatechin, or epicatechin), or any mixture thereof. In oneaspect, the one or more antioxidants are present in the fatty acid fillsdescribed herein in an amount of about 0.01% to about 2%, by weight ofthe fatty acids.

In one embodiment described herein, the pharmaceutical compositioncontains not more than about 20 ppm, about 15 ppm or about 10 ppm ofheavy metals (e.g., Pb, Hg, Bi, As, Sb, Sn, Cd, Ag, Cu, or Mo; e.g., USPtest 231). In another embodiment described herein, the pharmaceuticalcomposition described herein contains not more than 5 ppm, 4 ppm, 3 ppm,or 2 ppm of arsenic. In another embodiment described herein, thepharmaceutical composition described herein has a peroxide value notmore than about 10 meq/kg, 9 meq/kg, 8 meq/kg, 7 meq/kg, 6 meq/kg, 5meq/kg, about 4 meq/kg, about 3 meq/kg, or about 2 meq/kg. U.S. PatentApplication Publication No. US 2010/0278879, which is incorporated byreference herein for its specific teachings of heavy metal levels andperoxide values.

In another embodiment described herein, the pharmaceutical compositiondescribed herein comprising the fatty acids described herein having abaseline or first peroxide value not more than about 10 meq/kg, 9meq/kg, 8 meq/kg, 7 meq/kg, 6 meq/kg, 5 meq/kg, about 4 meq/kg, about 3meq/kg, or about 2 meq/kg, wherein upon storage of the saidpharmaceutical composition at about 30° C. and about 65% relativehumidity for a period about 1 month, about 2 months, about 3 months,about 4 months, about 5 months, about 6 months, about 7 months, about 8months, about 9 months, about 10 months, about 11 months, about 12months, about 13 months, about 14 months, about 15 months, about 16months, about 17 months, about 18 months, about 19 months, about 20months, about 21 months, about 22 months, about 23 months or about 24months, said pharmaceutical composition has a second peroxide value notgreater than about 25 meq/kg, about 24 meq/kg, about 23 meq/kg, about 22meq/kg, about 21 meq/kg, about 20 meq/kg, about 19 meq/kg, about 18meq/kg, about 17 meq/kg, about 16 meq/kg, about 15 meq/kg, about 14meq/kg, about 13 meq/kg, about 12 meq/k meq/kg g, about 11 meq/kg, about10 meq/kg, about 9 meq/kg, about 8 meq/kg, about 7 meq/kg, about 6meq/kg, about 5 meq/kg, about 4 meq/kg, about 3 meq/kg or about 2meq/kg.

The “baseline peroxide value” and “second peroxide values” can bemeasured in any suitable manner, for example by using any one of U.S.Pharmacopeia, Pharmacopeia Europe, or Japanese Pharmacopeia compendialmethods. Typically, a plurality of encapsulated EPA compositions isprovided, each composition containing EPA having been encapsulated atsubstantially the same time. A first sampling of one or more capsulesfrom the plurality is provided, the capsules are opened, and peroxidevalue of the EPA is measured substantially immediately thereafter,providing an average baseline peroxide value. At substantially the sametime, a second sampling of one or more capsules from the plurality isprovided and is placed under desired storage conditions for a desiredtime period. At the end of the desired time period, the capsules areopened and peroxide value of the EPA is measured substantiallyimmediately thereafter, providing an average second peroxide value. Thebaseline and second peroxide values can then be compared. In oneembodiment, the “baseline peroxide value” and “second peroxide value”are determined using a plurality of encapsulated EPA dosage unitswherein each dosage unit was encapsulated (e.g., the EPA is filled andsealed into capsules) within a same 60 day period, same 30 day period, asame 20 day period, a same 10 day period, a same 5 day period or a same1 day period.

One embodiment described herein, is a pharmaceutical compositioncomprising an enteric soft capsule comprising one or more film formingpolymers, one or more enteric polymers, one or more plasticizers, one ormore alkali neutralizing agents, one or more solvents, and optionallyone or more biomaterials, colorings, gelling agents, flavorings, orother conventionally accepted pharmaceutical excipients or additives. Inone aspect, enteric soft capsule composition described herein furthercomprises an active pharmaceutical ingredient in a matrix fill.

The enteric soft capsules described herein can be used for oral deliveryof active pharmaceutical ingredients, pharmaceutical agents,nutraceuticals, or nutritionals that are irritating to the stomach, thatare sensitive to the acidity of the stomach, or that have unpleasanttastes or odors. The enteric soft capsules described herein do notdissolve in the gastric environment (pH ca. 1.2), but readily dissolvein the intestinal environment (pH ca. 6.8).

One embodiment described herein is an all-natural enteric soft capsulecomposition comprising a gelatin composition ionically bonded withanionic enteric polymers. The enteric soft capsule shell can compriseone or more types of gelatin, one or more anionic enteric polymers, oneor more plasticizers, one or more solvents, and optionally colorings,gelling agents, flavorings, or other conventionally acceptedpharmaceutical excipients or additives.

Enteric soft capsules are described generally in International PatentApplication Publication Nos. WO 2004/030658 and WO 2007/075475 and U.S.Patent Application Publication Nos. US 2006/0165778 and US 2010/0158958,each of which is incorporated by reference herein for such teachings.

Useful film forming polymers can be a natural, synthetic orsemi-synthetic film forming polymer. Examples of film-former polymersthat are of a natural origin, include but are not limited to gelatin andcarrageenan. Suitable synthetic and semi-synthetic film forming polymersinclude, for example, hydroxypropyl methyl cellulose, methyl cellulose,hydroxypropyl methyl cellulose acetate succinate, hydroxypropyl methylcellulose phthalate, and cellulose acetate phthalate.

Gelatin compositions that are useful for creating enteric soft capsulesdescribed herein can be classified as either Type A or Type B gelatin.Examples of gelatin compositions that are useful for creating entericsoft capsule shells as described herein comprise acid bone gelatin, pigskin gelatin, chicken skin gelatin, fish gelatin, acid hide gelatin,gelatin hydrolysate, lime bone gelatin or combinations thereof. Type Agelatin is derived from the acid hydrolysis of collagen (e.g., acid bonegelatin or pig skin gelatin), while Type B gelatin (e.g., lime bonegelatin) is derived from the alkaline hydrolysis of collagen.Traditionally, bovine bones and skins have been used as raw materialsfor manufacturing Type A and Type B gelatin while porcine skins havebeen used extensively for manufacturing Type A gelatin. In general, acidprocessed gelatins form stronger gels than lime-processed gelatins ofthe same average molecular weight. In addition, at neutral pH values,Type A gelatins (acid processed gelatins) are typically net cationic andType B gelatins (alkali processed gelatins) are typically net anionic.The strength of said gelatin compositions are often defined by theirBloom strength or grade in the range of about 30 Bloom to about 400Bloom. In one embodiment, the gelatin Bloom strength is from about 50 toabout 200, including each integer in the specified range. In one aspect,the Bloom strength of the gelatin is about 100 Bloom. In one aspect, theBloom strength of the gelatin is about 125 Bloom. In one aspect, theBloom strength of the gelatin is about 150 Bloom. In another aspect, theBloom strength of the gelatin is about 175 Bloom. In another aspect, theBloom strength of the gelatin is about 190 Bloom.

Examples of film-former polymers that are useful for creatingnon-animal/non-gelatin enteric soft capsules described herein are kappacarrageenan, iota carrageenan, lambda carrageenan, or combinationsthereof.

Useful plasticizers as described herein comprise polyalcohols with 3 to6 carbon atoms, glycerol, sorbitol, Sorbitol Special® (SPI Pharma),non-crystallizing sorbitol, Polysorb® sorbitol 85/70/00 (Roquette), cornsyrup, polyethylene glycol, 1,2-propylene glycol, acetyl triethylcitrate, dibutyl phthalate, dibutyl sebacate, triacetine, polydextrose,maltodextrin, citric acid, citric acid esters, such as triethyl citrate,or combinations thereof. The weight ratios between the film formingpolymer, the acid-insoluble enteric polymer, filler, and plasticizer areadjusted so that the gel mass is flowable and not too viscous, and canbe made into enteric soft capsules. In one particular embodimentdescribed herein, the plasticizer comprises at least one of glycerol,sorbitol, corn syrup, malatol, triethyl citrate, or mixtures orcombinations thereof.

Examples of enteric, acid-insoluble polymers or enteric polymers areacrylic and methacrylate acid copolymers, cellulose acetate phthalate(CAP), cellulose acetate butyrate, hydroxypropylmethylcellulosephthalate (HPMCP), alginic acid salts such as sodium or potassiumalginate, or shellac. Acrylic and methacrylate acid copolymers areanionic copolymers based on methacrylic acid and methyl methacrylatethat are particularly stable and are preferred in one embodiment.Acrylic and methacrylate acid copolymers available under the trade nameEUDRAGIT® (Evonik Industries AG, Essen, Germany) are provided as powderor aqueous dispersions, and in one aspect, can be EUDRAGIT® L 30 D-55;EUDRAGIT® L 100-55; EUDRAGIT® L 100; EUDRAGIT® L 12.5; EUDRAGIT® S 100;EUDRAGIT® S 12.5; EUDRAGIT® FS 30 D; EUDRAGIT® E 100; EUDRAGIT® E 12.5;EUDRAGIT® E PO; EUDRAGIT® RL 100; EUDRAGIT® RL PO; EUDRAGIT® RL 30 D;EUDRAGIT® RL 12.5; EUDRAGIT® RS 100; EUDRAGIT® RS PO; EUDRAGIT® RS 30 D;EUDRAGIT® RS 12.5; EUDRAGIT® NE 30 D; EUDRAGIT® NE 40 D; EUDRAGIT® NM 30D; other poly(meth)acrylate polymers; or a mixture thereof.Acid-insoluble polymer specifications are detailed in the United StatesPharmacopoeia and in various monographs.

In one embodiment described herein, the enteric polymer in the entericsoft capsule shell comprises poly(methacylic acid-co-methylmethacrylate) 1:1 (e.g., EUDRAGIT® L 100). In one embodiment describedherein, the enteric polymer in the enteric soft capsule shell comprisespoly(methacylic acid-co-ethyl acrylate) 1:1 (e.g., EUDRAGIT® L 100-55).In one embodiment described herein, the enteric polymer comprisespoly(ethyl acrylate-co-methyl methacrylate) 2:1 (e.g., EUDRAGIT® NE 40D). In another embodiment described herein, the enteric polymercomprises poly(methyl acrylate-co-methyl methacrylate-co-methacrylicacid) 7:3:1 (e.g., EUDRAGIT® FS 30 D). In another embodiment describedherein the enteric polymer comprises a combination of poly(methacylicacid-co-ethyl acrylate) 1:1 and poly(methyl acrylate-co-methylmethacrylate-co-methacrylic acid) 7:3:1. In another embodiment, theenteric polymer comprises a combination of poly(methacylic acid-co-ethylacrylate) 1:1 and poly(ethyl acrylate-co-methyl methacrylate) 2:1. Inanother embodiment, the enteric polymer comprises a combination ofpoly(methacylic acid-co-ethyl acrylate) 1:1, poly(ethylacrylate-co-methyl methacrylate) 2:1, and poly(methyl acrylate-co-methylmethacrylate-co-methacrylic acid) 7:3:1.

In one embodiment, enteric soft capsule shells can be made by dissolvingthe enteric acid-insoluble polymer in an aqueous solution of an alkalineutralizing agent such as ammonia, sodium hydroxide, potassiumhydroxide, or liquid amines such as tri-ethanol amine or ethylenediamine. The amount of alkali is adjusted to give a final pH value ofthe gel mass less than or equal to about pH 9.0. In another embodiment,the final pH does not exceed 8.5. The film forming polymer can then becombined with the plasticizer and solvent and then blended with theacid-insoluble gel to make a final homogeneous mixture. In one aspect,sodium hydroxide is a preferred alkali neutralizing agent.

In another embodiment described herein, an enteric soft capsule shellcan be made by using an aqueous dispersion of the acid-insoluble polymeror polymers by adding alkaline materials such as ammonium, sodium, orpotassium hydroxides, other alkalis, or a combination thereof that willcause the enteric acid-insoluble polymer to dissolve. Theplasticizer-wetted, film forming polymer can then be mixed with thesolution of the acid-insoluble polymer. In one embodiment describedherein, enteric acid-insoluble polymers in the form of salts of theabove-mentioned bases or alkalis can be dissolved directly in water andmixed with the plasticizer-wetted, film forming polymer. In anotherembodiment described herein, an aqueous dispersion of the acid-insolublepolymer or polymers can be used, which obviates the need for theaddition of the aforementioned alkaline materials.

In another embodiment described herein, an enteric soft capsule shellcan be made using natural enteric, acid-insoluble anionic polymer. Inone aspect, the enteric acid-insoluble anionic polymer is an anionicpolysaccharide. In another aspect, the anionic polysaccharide comprisespolygalacturonic acid, carboxymethyl pullulan, carboxymethyl cellulose,hyaluronic acid, cellulose phthalate, cellulose succinate, alginate,sodium alginate, or pectin. In another aspect described herein, theanionic polysaccharide comprises pectin. Acid-insoluble specificationsof enteric capsules are detailed in the United States Pharmacopoeia andin various monographs.

In one embodiment described herein, enteric soft capsules may optionallycomprise fillers or bulking agents comprising hydroxypropyl starchphosphate, acacia, alginic acid, microcrystalline cellulose,carboxymethylcellulose, hydroxypropyl methylcellulose, methylcellulose,ethylcellulose, pregelatinized starch, potato starch, tapioca starch,rice starch, corn starch, wheat starch, pea starch, modified starches,pregelatinized starch, microcrystalline cellulose, hydroxypropylmethylcellulose, lactose, dextrates, dextrin, dextrose, maltodextrin,glucose, sucrose, powdered sugar, sucrose syrup, mannitol, gums likexanthan gum, tragacantha, guar gum, acacia gum, arabic gum, ferulagummosa boiss, gum olibanum, beilschmiedia seed gum, aegle marmelos gum,okra gum, cassia roxburghii seeds gum, kaolin, talc, bentonite, calciumphosphates, calcium carbonate, magnesium carbonate, magnesium oxide,calcium sulphate, hydrogenated sodium chloride, potassium chloride,combinations or mixtures thereof, and others known in the art. Otheruseful fillers are N-Lok®, (starch sodium octenyl succinate), Hi-Cap™,and Ultra Sperse® M.

In one embodiment, optional gelling agents can be added to the entericsoft capsules. The addition of gelling agents is optional and depends onthe gelatin type (e.g., Type B gelatin), which may function to increasethe overall strength of the capsule shell. Without being bound to anytheory, it is believed that the cationic gelling agent promotes an ionicinteraction between the gelatin composition and anionic enteric polymersdescribed herein. Suitable gelling agents as described herein comprisemono or divalent cations, such as calcium, sodium, potassium, magnesium,or their salt forms comprising calcium sulfate, sodium chloride,potassium sulfate, sodium carbonate, lithium chloride, sodium borate,potassium bromide, potassium fluoride, sodium bicarbonate, calciumchloride, magnesium chloride, sodium citrate, sodium acetate, calciumlactate, magnesium sulfate, sodium fluoride, or mixtures thereof.

In one embodiment described herein, the enteric capsule shells canoptionally, include one or more viscosity modifiers. Examples ofsuitable viscosity modifiers include guar gum, locust bean gum, xanthangum, agar, and gellan gum. The viscosity modifier can be included in thecapsule shell in an amount of greater than 0.01% by weight and less than10% by weight of the dried capsule shell (e.g., less than 9%, less than8%, less than 7%, less than 6%, less than 5%, less than 4%, less than3%, less than 2%, less than 1%, or less than 0.5% by weight of the driedcapsule shell).

The enteric capsule shell can be prepared as a transparent ortranslucent enteric capsule shell. In one embodiment, the entericcapsule shell can be semi-transparent, semi-opaque, or opaque.Optionally, the opaque enteric capsule shells are prepared usingtitanium dioxide, which can protect light sensitive active ingredientsfrom degradation. The enteric capsule shells can further include acolorant to color the capsules. Examples of suitable colorants includeFD&C and D&C dyes, iron oxides, and natural colorants. Optionally, thecapsule can be imprinted or have a decorative coating. The entericcapsule shell can be prepared to have only one compartment (i.e., theenteric capsule shell does not contain multiple compartments).

Useful sealants that impart moisture protection to the capsule shellinclude but are not limited to a methacrylic acid copolymer,hydroxypropylmethylcellulose, or a proprietary sealant such asKollicoat® Protect (BASF). In one embodiment described herein, thesealant is Kollicoat® Protect.

In one embodiment described herein, the enteric soft capsule has thecomposition of Table 2, including all possible iterations of thespecified ranges that provide 100% for the total weight percentage,including or excluding the optional sealants, colorings, flavorings, orexcipients.

TABLE 2 Enteric Soft Capsule Shell Composition Composition ComponentExemplary Components Range (%) Film forming Gelatin 0.5-50  polymerEnteric-acid Anionic polysaccharide 0.25-20   insoluble or acrylic andpolymer methacrylic acid copolymers Plasticizer Glycerol and/or Sorbitoland/or  6-40 Triethyl citrate Alkali neutralizing NH₄OH (30%) or NaOH0.01-7   agent Gelling agent Calcium or Magnesium or 0.01-1   PotassiumFiller (bulking agent) Hydroxypropyl starch 10-20 phosphate SolventWater 10-70 Sealant (optional) Kollicoat ® Protect 1-5 Opacifier(optional) Titanium dioxide 0.5-5   Coloring (optional) Various0.005-1    Flavoring (optional) Various 0.005-2    Excipients (optional)Various 1-5

In another embodiment described herein, the film forming polymercomprises gelatin. In one embodiment, the weight percentage of the totalgelatin composition in the enteric soft gel composition comprises fromabout 10% to about 50% including all integers within the specifiedrange. In another embodiment, the weight percentage of the gelatincomposition in the gel mass comprises from about 13% to about 45%including all integers within the specified range. In anotherembodiment, the weight percentage of the gelatin composition in the gelmass comprises from about 28% to about 36%. In one aspect, the weightpercentage of the gelatin composition in the gel mass is about 29%. Inanother aspect, the weight percentage of the gelatin composition in thegel mass is about 33%. In another aspect, the weight percentage of thegelatin composition in the gel mass is about 35%. In another aspect, theweight percentage of the gelatin composition in the gel mass is about44%.

In another embodiment described herein, the weight percentage ratiorange of Type A gelatin to Type B gelatin in the enteric soft gelcomposition comprises from about 2:1 to about 11:1, including all ratioswithin the specified range. In one aspect, the weight percentage ratiorange of Type A gelatin to Type B gelatin in the gel mass is about 6:1.In another aspect, the ratio of Type A gelatin to Type B gelatin in thegel mass is about 3:1.

In another embodiment described herein, the weight percentage ratio ofType A gelatin to gelatin hydrolysate in the enteric soft gelcomposition comprises from about 10:1 to about 35:1, including allratios within the specified range. In one aspect, the weight percentageratio of Type A gelatin to gelatin hydrolysate in the gel mass is about12:1, including all integers within the specified range. In anotheraspect, the ratio of Type A gelatin to gelatin hydrolysate in the gelmass is about 27:1.

In another embodiment described herein, the weight percentage of Type Agelatin in the enteric soft gel composition comprises from about 22% toabout 38%, including all integers within the specified range. In anotherembodiment, the weight percentage of Type A gelatin in the gel masscomprises from about 28% to about 36%, including all integers within thespecified range. In one aspect, the weight percentage of Type A gelatinin the gel mass is about 28%. In another aspect, the weight percentageof Type A gelatin in the gel mass is about 31%. In another aspect, theweight percentage of Type A gelatin in the gel mass is about 33%.

In another embodiment described herein, the weight percentage of Type Bgelatin in the enteric soft gel composition comprises from about from22% to about 38%, including all integers within the specified range. Inanother embodiment, the weight percentage of Type B gelatin in the gelmass comprises from about from 28% to about 36%, including all integerswithin the specified range. In one aspect, the weight percentage of TypeB gelatin in the gel mass is about 28%. In another aspect, the weightpercentage of Type B gelatin in the gel mass is about 31%. In anotheraspect, the weight percentage of Type A gelatin in the gel mass is about33%. In another aspect, the weight percentage of Type A gelatin in thegel mass is about 36%.

In another embodiment described herein, the weight percentage of Type Bgelatin in the enteric soft gel composition comprises from about 1% toabout 10%, including all integers within the specified range. In anotherembodiment, the weight percentage of Type B gelatin in the gel masscomprises from about 1% to about 7%, including all integers within thespecified range. In one aspect, the weight percentage of Type B gelatinin the gel mass is about 3%. In another aspect, the weight percentage ofType B gelatin in the gel mass is about 7%. In another aspect, theweight percentage of Type B gelatin in the gel mass is about 9%.

In one embodiment, described herein, the weight percentage of entericacid insoluble polymer in the enteric soft gel composition comprisesfrom about 2% to about 30% of the enteric soft shell capsule.

In one embodiment described herein, the enteric acid insoluble polymercomprises a natural polymer. In one aspect, the natural enteric acidinsoluble polymer comprises an anionic polysaccharide. In one aspect,the anionic polysaccharide comprises pectin. In one aspect, the weightpercentage of pectin in the enteric soft gel composition comprises fromabout from 2% to about 7%, including all integers within the specifiedrange. In another aspect, the weight percentage of pectin in the gelmass is about 2%. In another aspect, the weight percentage of pectin inthe gel mass is about 3%. In another aspect, the weight percentage ofpectin in the gel mass is about 4%. In another aspect, the weightpercentage of pectin in the gel mass is about 5%. In another aspect, theweight percentage of enteric pectin in the gel mass is about 6%. Inanother aspect, the weight percentage of enteric pectin in the gel massis about 7%.

In another embodiment described herein, the enteric acid insolublepolymer comprises an enteric acid insoluble polymer comprisingpoly(meth)acrylates (methacrylic acid copolymer; e.g., EUDRAGIT®). Inone embodiment described herein, the weight percentage of enteric acidinsoluble polymer comprises from about 2% to about 30% including allintegers within the specified range. In another embodiment describedherein, the weight percentage of enteric acid insoluble polymercomprises from about 8% to about 15% including all integers within thespecified range. In one aspect, the weight percentage of enteric acidinsoluble polymer is about 9.5%. In another aspect, the weightpercentage of enteric acid insoluble polymer is about 11%. In anotheraspect, the weight percentage of enteric acid insoluble polymer is about14%.

In one embodiment described herein, the weight percentage ofpoly(methacylic acid-co-ethyl acrylate) 1:1 in the enteric soft capsulegel mass composition comprises from about 2% to about 15%, including alliterations of integers within the specified range. In one aspect, theweight percentage of poly(methacylic acid-co-ethyl acrylate) 1:1 in thegel mass is about 6%. In another aspect, the weight percentage ofpoly(methacylic acid-co-ethyl acrylate) 1:1 in the gel mass is about 9%.In another aspect, the weight percentage of poly(methacylicacid-co-ethyl acrylate) 1:1 in the gel mass is about 11%. In anotheraspect, the weight percentage of poly(methacylic acid-co-ethyl acrylate)1:1 in the gel mass is about 13%.

In one embodiment described herein, the weight percentage of poly(ethylacrylate-co-methyl methacrylate) 2:1 in the enteric soft capsule gelmass comprises from about 0.25% to about 4%, including all iterations ofintegers within the specified range. In one aspect, the weightpercentage of poly(ethyl acrylate-co-methyl methacrylate) 2:1 in the gelmass is about 0.25%. In another aspect, the weight percentage ofpoly(ethyl acrylate-co-methyl methacrylate) 2:1 in the gel mass is about2%. In another aspect, the weight percentage of poly(ethylacrylate-co-methyl methacrylate) 2:1 in the gel mass is about 4%.

In one embodiment described herein, the weight percentage of poly(methylacrylate-co-methyl methacrylate-co-methacrylic acid) 7:3:1 in theenteric soft capsule gel mass comprises from about 1% to about 14%,including all iterations of integers within the specified range. In oneaspect, the weight percentage of poly(methyl acrylate-co-methylmethacrylate-co-methacrylic acid) 7:3:1 in the gel mass is about 1%. Inanother aspect, the weight percentage of poly(methyl acrylate-co-methylmethacrylate-co-methacrylic acid) 7:3:1 in the gel mass is about 5%. Inanother aspect, the weight percentage of poly(methyl acrylate-co-methylmethacrylate-co-methacrylic acid) 7:3:1 in the gel mass is about 8%. Inanother aspect, the weight percentage of poly(methyl acrylate-co-methylmethacrylate-co-methacrylic acid) 7:3:1 in the gel mass is about 12%. Inanother aspect, the weight percentage of poly(methyl acrylate-co-methylmethacrylate-co-methacrylic acid) 7:3:1 in the gel mass is about 14%.

In one embodiment, the alkali neutralizing-agent is ammonia (ammoniumhydroxide; 30% w/v) that is added to comprise a weight percentage fromabout 1% to about 5% of the total enteric soft capsule gel mass. In oneaspect, 30% w/v ammonia is added to comprise a weight percentage ofabout 2% of the gel mass. In another aspect, 30% w/v ammonia is added toa weight percentage of about 1.7% of the gel mass. In another aspect,ammonia is added to provide a final pH of about 9 in the enteric softcapsule gel mass. In another aspect, ammonia is added to provide a finalpH of about 8.5 in the enteric soft capsule gel mass. In another aspect,after the capsules are filled and dried, the ammonia concentration issubstantially reduced, owing to the fugitive nature of the volatilealkali. In another aspect, practically all of the ammonia is evaporatedexcept for ammonium ions comprising salts with other moieties in the gelmass composition.

In one aspect, 30% w/v ammonia is added to comprise a weight percentageof about 2% of the gel mass. In another aspect, 30% w/v ammonia is addedto comprise a weight percentage of about 3.5% of the gel mass.

In one embodiment described herein, the solvent comprises from about 10%to about 70% of the enteric soft capsule composition, including allintegers within the specified range. In one embodiment, the solventcomprises water. The quantity of water in the composition variesdepending on the quantities of the other ingredients. For example, thequantity of opacifier, coloring, flavoring, or other excipients canchange the percentage of water present in the composition. In oneembodiment, the weight percentage of water comprises as much as sufficesto bring the total weight percentage to 100% (i.e., quantum sufficiat;q.s.). In another embodiment, the water comprises about 70%, about 60%,about 50%, about 40%, about 30%, about 20% or about 10%, of the entericsoft capsule composition. In one aspect, water comprises about 45% ofthe enteric soft capsule composition. In one aspect, water comprisesabout 46% of the enteric soft capsule composition. In one aspect, watercomprises about 44% of the enteric soft capsule composition.

In one embodiment described herein, the final moisture (water) contentof the enteric soft capsule shell formed from the compositions describedherein comprises from about 8% to about 20%, including all integerswithin the specified range. In another embodiment, the moisture contentof the enteric soft capsule shell comprises from about 8% to about 12%,including all integers within the specified range. In one aspect, thefinal moisture content of the enteric soft capsule shell is about 8%. Inone aspect, the final moisture content of the enteric soft capsule isabout 9%. In one aspect, the final moisture content of the enteric softcapsule shell is about 10%. In one aspect, the final moisture content ofthe enteric soft capsule shell is about 11%. In another aspect, thefinal moisture content of the enteric soft capsule shell is about 12%.

In one embodiment described herein, the weight percentage range of totalplasticizer in the enteric soft capsule composition comprises from about6% to about 40%, including all iterations of integers within thespecified range. In another embodiment, the weight percentage range oftotal plasticizer in the gel mass comprises from about 3% to about 20%,including all iterations of integers within the specified range. Inanother embodiment, the weight percentage range of total plasticizer inthe gel mass comprises from about 9% to about 18%, including alliterations of integers within the specified range. In one aspect, thetotal plasticizer weight percentage in the gel mass is about 11%. Inanother aspect, the total plasticizer weight percentage is about 13%. Inanother aspect, the total plasticizer weight percentage in the gel massis about 15%. In another aspect, the total plasticizer weight percentagein the gel mass is about 16%. In another aspect, the total plasticizerweight percentage in the gel mass is about 17%. In another aspect, thetotal plasticizer weight percentage in the gel mass is about 18%.

In one embodiment described herein, the weight percentage range offiller or bulking agent in the enteric soft capsule compositioncomprises from about 8% to about 20%, including all iterations ofintegers within the specified range. In another embodiment, the weightpercentage range of filler in the gel mass comprises from about 9% toabout 14%, including all iterations of integers within the specifiedrange. In another embodiment, the weight percentage range of filler inthe gel mass comprises from about 9% to about 12%, including alliterations of integers within the specified range. In one aspect, thefiller weight percentage in the gel mass is about 13%. In anotheraspect, the filler weight percentage in the gel mass is about 12%. Inanother aspect, the total plasticizer weight percentage is about 11%. Inanother aspect, the filler weight percentage in the gel mass is about10%. In one aspect, the filler weight percentage is about 9%. In anotheraspect, the total plasticizer weight percentage in the gel mass is about9.2%.

In one embodiment described herein, the weight percentage range ofgelling agent in the enteric soft capsule composition comprises fromabout 0.001% to about 1%, including all iterations of integers withinthe specified range. In one aspect, the weight percentage range ofgelling agent in the gel mass is about 0.001%. In another aspect, theweight percentage range of gelling agent in the gel mass is about0.005%. In another aspect, the weight percentage range of gelling agentin the gel mass is about 0.01%. In another aspect, the weight percentagerange of gelling agent in the gel mass is about 0.025%. In anotheraspect, the weight percentage range of gelling agent in the gel mass isabout 0.05%. In another aspect, the weight percentage range of gellingagent in the gel mass is about 0.075%. In another aspect, the weightpercentage range of gelling agent in the gel mass is about 0.1%. Inanother aspect, the weight percentage range of gelling agent in the gelmass is about 0.5%. In another aspect, the weight percentage range ofgelling agent in the gel mass is about 1%.

In one embodiment described herein, the alkali neutralizing agent isammonia (e.g., ammonium hydroxide; 30% w/v) that is added to comprise aweight percentage from about 1% to about 5% of the total enteric softcapsule composition. The ammonia is added neat and dilution is notconsidered in calculating the weight percentage; thus, the weightpercentage indicated is the weight percentage of 30% ammonium hydroxideadded to the composition. In one aspect, ammonia comprises a weightpercentage of about 2% of the gel mass. In another aspect, ammoniacomprises a weight percentage of about 1.7% of the gel mass. In oneaspect, ammonia is added to provide a final pH of about 9 in the entericsoft capsule composition. In another aspect, ammonia is added to providea final pH of about 8.5 in the enteric soft capsule composition. Inanother aspect, after the capsules are filled and dried, the ammoniaconcentration is substantially reduced, owing to the fugitive nature ofthe volatile alkali. In some aspects, practically all of the fugitiveammonia is evaporated from the gel mass except for ammonium ionscomprising salts with other components of the composition.

In one embodiment, the alkali neutralizing-agent is a 40 mg/mL solutionof sodium hydroxide (NaOH 1 M) that is added to comprise a weightpercentage of about 1% to about 7% of the total enteric soft capsule gelmass corresponding to a final concentration of NaOH from about 0.4 mg/mLto about 2.8 mg/mL of NaOH. In one aspect, the amount of 1 M NaOH isadded to comprise about 2% of the total enteric soft capsule gel masscorresponding to a final concentration of NaOH of about 0.8 mg/mL. Inanother aspect, the amount of 1 M NaOH is added to comprise about 3.5%of the total enteric soft capsule gel mass corresponding to a finalconcentration of NaOH of about 1.4 mg/mL. In another aspect, the amountof 1 M NaOH is added to comprise about 5% of the total enteric softcapsule gel mass corresponding to a final concentration of NaOH of about2 mg/mL.

In one embodiment described herein, the weight percentage range of totalgelatin based (total gelatin content and enteric-acid insoluble polymer)of the enteric soft capsule composition described herein comprises fromabout 12% to about 70%, including all integers within the specifiedrange. In one embodiment, the weight percentage range of total polymercontent of the enteric soft capsule composition described hereincomprises from about 25% to about 50%, including all integers within thespecified range. In one aspect, the total cross-linked polymer weightpercentage in the gel mass is about 31%. In another aspect, the totalcross-linked polymer weight percentage in the gel mass is about 35%. Inanother aspect, the total cross-linked polymer weight percentage in thegel mass is about 40%. In another aspect, the total cross-linked polymerweight percentage in the gel mass is about 45%.

In one embodiment described herein, the weight percentage range of totalionically bonded polymer content (total gelatin content and anionicpolymer (e.g., an anionic polysaccharide) of the enteric soft capsulecomposition described herein comprises from about 28% to about 41%,including all integers within the specified range. In one aspect, thetotal ionically bonded polymer weight percentage in the gel mass isabout 31%. In another aspect, the total ionically bonded polymer weightpercentage in the gel mass is about 35%. In another aspect, the totalionically bonded polymer weight percentage in the gel mass is about 40%.

In one embodiment, the weight ratio range of gelatin film formingpolymer to enteric acid insoluble polymer (gelatin film forming:enteric) comprises about 1:2 to about 25:1, including all ratios withinthe specified range. In one embodiment, the weight ratio range ofgelatin film forming polymer to enteric acid insoluble polymer (gelatinfilm forming: enteric) comprises from about 1:1 (≈1) to about 10:1,including all ratios within the specified range. In one embodiment, theweight ratio range of gelatin film forming polymer to enteric acidinsoluble polymer (gelatin film forming: enteric) comprises from about3:1 to about 7:1, including all ratios within the specified range. Inone aspect, the ratio of gelatin film forming polymer to enteric acidinsoluble polymer is about 3:1 In another aspect, the ratio of gelatinfilm forming polymer to enteric acid insoluble polymer is about 5:1. Inanother aspect, the ratio of gelatin film forming polymer to entericacid insoluble polymer is about 6.5:1.

In one embodiment, the weight ratio range of poly(methacylicacid-co-ethyl acrylate) 1:1 to total enteric polymer in the enteric softcapsule gel mass comprises from about 1:7 to about 1:1. In one aspect,the weight ratio of poly(methacylic acid-co-ethyl acrylate) 1:1 to totalenteric polymer in the enteric soft capsule gel mass is about 1:1.

In one embodiment, the weight ratio range of poly(ethylacrylate-co-methyl methacrylate) 2:1 to total enteric polymer in theenteric soft capsule gel mass comprises from about 1:50 to about 1:4. Inone aspect, the weight ratio of poly(ethyl acrylate-co-methylmethacrylate) 2:1 to total enteric polymer in the enteric soft capsulegel mass is about 1:50.

In one embodiment, the weight ratio range of poly(methylacrylate-co-methyl methacrylate-co-methacrylic acid) 7:3:1 to totalenteric polymer in the enteric soft capsule gel mass comprises fromabout 1:6 to about 1:1. In one aspect, the weight ratio of poly(methylacrylate-co-methyl methacrylate-co-methacrylic acid) 7:3:1 to totalenteric polymer in the enteric soft capsule gel mass is about 1:1.3.

In one embodiment, the weight ratio range of poly(methacylicacid-co-ethyl acrylate) 1:1 to poly(ethyl acrylate-co-methylmethacrylate) 2:1 in the enteric soft capsule gel mass comprises fromabout 1:1 to about 44:1, including all iterations of ratios within thespecified range. In one aspect, the weight ratio of poly(methacylicacid-co-ethyl acrylate) 1:1 to poly(ethyl acrylate-co-methylmethacrylate) 2:1 in the enteric soft capsule gel mass is about 44:1.

In one embodiment, the weight ratio range of poly(methacylicacid-co-ethyl acrylate) 1:1 to poly(methyl acrylate-co-methylmethacrylate-co-methacrylic acid) 7:3:1 in the enteric soft capsule gelmass comprises from about 1:6 to about 5:1, including all iterations ofratios within the specified range. In one aspect, the weight ratio ofpoly(methacylic acid-co-ethyl acrylate) 1:1 to poly(methylacrylate-co-methyl methacrylate-co-methacrylic acid) 7:3:1 in theenteric soft capsule gel mass is about 1:4. In another aspect, the ratioof poly(methacylic acid-co-ethyl acrylate) 1:1 to poly(methylacrylate-co-methyl methacrylate-co-methacrylic acid) 7:3:1 in the gelmass is about 4:1. In another aspect, the ratio of poly(methacylicacid-co-ethyl acrylate) 1:1 to poly(methyl acrylate-co-methylmethacrylate-co-methacrylic acid) 7:3:1 in the gel mass is about 7.5:1.

In one embodiment, the enteric soft capsule gel masses described herein,are unexpectedly more flowable and less viscous than soft capsule gelmasses generated with structurally similar poly(methacylicacid-co-methyl methacrylate) anionic copolymers (e.g., poly(methacylicacid-co-methyl methacrylate) 1:1). In one aspect, the aforementionedabove gel masses result in enteric soft capsules that are less brittleand more efficiently generated through rotary die encapsulation methodsknown in the art.

In another embodiment described herein, enteric soft capsule gel massescan be generated to be even less viscous and more flowable with acombination of poly(methacylic acid-co-ethyl acrylate) 1:1 andpoly(ethyl acrylate-co-methyl methacrylate) 2:1.

In another embodiment described herein, enteric soft capsules generatedfrom gel masses comprising poly(methacylic acid-co-ethyl acrylate) 1:1and poly(methyl acrylate-co-methyl methacrylate-co-methacrylic acid)7:3:1 as described herein comprise modified release profiles (e.g.,release at pH greater than 7.0 or colonic release). In one aspect, theratio of poly(methacylic acid-co-ethyl acrylate) 1:1 to poly(methylacrylate-co-methyl methacrylate-co-methacrylic acid) 7:3:1 in theenteric soft capsule shell gel masses is adjusted to determine thelocation in the gastro-intestinal tract where capsule shell dissolutionoccurs. In another aspect, ratios of poly(methacylic acid-co-ethylacrylate) 1:1 to poly(methyl acrylate-co-methylmethacrylate-co-methacrylic acid) 7:3:1 of at least about 1:3 or greaterin the gel mass promote capsule shell dissolution at higher pH values.

In one embodiment, the weight ratio range of alkali neutralizing-agentto enteric polymer in the enteric soft capsule gel mass comprises fromabout 1:14 to about 1:1.7, including all iterations of ratios within thespecified range. In one aspect, the ratio of alkali neutralizing-agentto enteric polymer in the gel mass is about 5:1. In another aspect, theratio of alkali neutralizing-agent to enteric polymer in the gel mass isabout 1:6. In another aspect, the ratio of alkali neutralizing-agent toenteric polymer in the gel mass is about 1:4. In another aspect, theratio of alkali neutralizing-agent to enteric polymer in the gel mass isabout 1:3.

In one embodiment described herein, the weight percentage ratio range oftotal gelatin to anionic polymer of the enteric soft capsule compositiondescribed herein comprises from about 4:1 to about 19:1, including allratios within the specified range. In one aspect, the weight percentageratio of total gelatin to anionic polymer in the gel mass is about 4:1.In one aspect, the weight percentage ratio of total gelatin to anionicpolymer in the gel mass is about 6:1. In one aspect, the weightpercentage ratio of total gelatin to anionic polymer in the gel mass isabout 10:1. In one aspect, the weight percentage ratio of total gelatinto anionic polymer in the gel mass is about 12:1. In one aspect, theweight percentage ratio of total gelatin to anionic polymer in the gelmass is about 15:1. In one aspect, the weight percentage ratio of totalgelatin to anionic polymer in the gel mass is about 19:1.

In one embodiment, the weight ratio range of gelatin to plasticizercomprises from about 1:4 to about 9:1, including all ratios within thespecified range. In one embodiment, the weight ratio range of gelatin toplasticizer comprises from about 1:2 to about 5:1, including all ratioswithin the specified range. In one embodiment, the weight ratio range ofgelatin to plasticizer comprises from about 1:1 to about 3:1, includingall ratios within the specified range. In one aspect, the weight ratioof gelatin to plasticizer is about 1.6:1. In another aspect, the weightratio of plasticizer to enteric acid insoluble polymer is about 2:1.

In one embodiment described herein, the weight ratio range of totalplasticizer to total polymer (i.e., film forming and enteric) in theenteric soft gel composition comprises from about 1:11.5 (≈0.87) toabout 3:1, including all ratios within the specified range. In oneembodiment described herein, the weight ratio range of total plasticizerto total polymer (i.e., film forming and enteric) in the enteric softgel composition comprises from about 1:7 to about 2:1, including allratios within the specified range. In one embodiment described herein,the weight ratio range of total plasticizer to total polymer (i.e., filmforming and enteric) in the enteric soft gel composition comprises fromabout 1:1 to about 2:1, including all ratios within the specified range.In one aspect, the weight ratio range of total plasticizer to totalpolymer in the gel mass is about 1:1. In another aspect, the weightratio range of total plasticizer to total polymer in the gel mass isabout 1.6:1.

In one embodiment described herein, the weight ratio range of totalplasticizer to total polymer (i.e., film forming and enteric) in theenteric soft gel composition comprises from about 1:2 to about 1:1.1(i.e., ≈0.50-0.9), including all ratios within the specified range. Inone aspect, the weight ratio range of total plasticizer to total polymerin the gel mass is about 1:1.25 (≈0.80). In another aspect, the weightratio range of total plasticizer to total polymer in the gel mass isabout 1:1.4 (≈0.7). In another aspect, the weight ratio range of totalplasticizer to total polymer in the gel mass is about 1.1.6 (≈0.6). Inanother aspect, the weight ratio range of total plasticizer to totalpolymer in the gel mass is about 1:2 (≈0.5).

In one embodiment described herein, the weight ratio range of totalplasticizer to filler or bulking agent (e.g., hydroxypropyl starchphosphate) in the enteric soft gel composition comprises from about1:1.16 to about 1.2:1 (≈0.6-1.2), including all ratios within thespecified range. In one aspect, the weight ratio of total plasticizer toenteric polymer in the gel mass is about 1.1:1 (≈1.1). In anotheraspect, the weight ratio of total plasticizer to enteric polymer in thegel mass is about 1:1.1 (≈0.9). In another aspect, the weight ratio oftotal plasticizer to enteric polymer is about 1:1.14 (≈0.7). In anotheraspect, the weight ratio of total plasticizer to enteric polymer in thegel mass is about 1:1.16 (≈0.6).

In one embodiment, the weight ratio range of plasticizer to enteric acidinsoluble polymer (plasticizer: enteric) comprises from about 1:5 toabout 20:1, including all ratios within the specified range. In oneembodiment, the weight ratio range of plasticizer to enteric acidinsoluble polymer (plasticizer: enteric) comprises from about 1:2 toabout 5:1, including all ratios within the specified range. In oneembodiment, the weight ratio range of plasticizer to enteric acidinsoluble polymer (plasticizer: enteric) comprises from about 1:1 toabout 2:1, including all ratios within the specified range. In oneaspect, the ratio of plasticizer to enteric acid insoluble polymer isabout 5:3 (≈1.7). In another aspect, the ratio of plasticizer to entericacid insoluble polymer is about 1:1.

In one embodiment described herein, the weight ratio range of entericpolymer to filler (e.g., hydroxypropyl starch phosphate) in the entericsoft gel composition comprises from about 1:1.4 (≈0.7) to about 1.2:1(≈1.2) (i.e., ≈0.7-1.2), including all ratios within the specifiedrange. In some aspects, the ratio of film forming polymer to filler inthe gel mass is about 1:1.4 (≈0.7), about 1:1.25 (≈0.8), about 1:1.1(≈0.9), about 1:1 (≈1), or about 1.1:1 (≈1.1). In one aspect, the ratioof film forming polymer to filler in the gel mass is about 1.1:1 (≈1.1).

One embodiment described herein provides an enteric acid-insolublepolymer dispersed within the film-forming polymer gel mass that providesthe total soft gel composition with enteric acid-insoluble properties,at relatively low concentrations of the enteric acid-insoluble polymer(e.g., from about 8% to about 20% of the total wet gel mass composition)and without the need of excessive amounts of alkali, thus avoidingdenaturation or degradation of the film-forming polymer that can weakenthe integrity of the enteric soft capsule shell.

Films of the enteric soft capsule shell do not dissolve or disintegratein acids, such as 0.1 N hydrochloric acid or simulated gastric fluid(ca. pH 1.2), despite the fact that the majority of the shellingredients (i.e., greater than 50%) normally dissolve in, or aremiscible with, acids. Enteric soft capsules made using the compositionsdescribed herein remain intact in hydrochloric acid or simulated gastricfluid for at least two hours. The capsules readily release the contentsupon shifting the pH of the solution to ca. 6.8, such as that ofsimulated intestinal fluid.

In another embodiment, the final enteric capsule composition providesfilms of increased strength without substantially compromising filmelasticity. Moreover, films made from the enteric soft capsulecompositions as described herein are sealed at normal temperature rangetypically used for making traditional soft gel capsules. In one aspect,enteric soft capsules are made using a rotary die apparatus as describedin U.S. Pat. Nos. 5,459,983; 5,146,730; and 6,482,516, each of which areincorporated by reference herein for such teachings.

Another embodiment described herein includes a process of manufacturingenteric soft capsules comprising the pharmaceutical composition asdescribed herein. The process includes preparing a gel mass compositioncomprising a film-forming, water-soluble polymer and an entericacid-insoluble polymer and mixing with appropriate plasticizers andsolvent; casting the gel mass into films or ribbons usingheat-controlled drums or surfaces; and manufacturing an enteric softcapsule comprising a pharmaceutical composition using rotary dietechnology. The thickness of the films or ribbons that form the entericcapsule shell is from about 0.010 inches (≈0.254 mm) to about 0.050inches (≈1.27 mm), including all integers within the specified range.The shell thickness comprises about 0.010 inch (≈0.254 mm), about 0.015inch (≈0.381 mm), about 0.02 in (≈0.508 mm), about 0.03 in (≈0.762 mm),about 0.04 in (≈1.02 mm), or about 0.05 in (≈1.27 mm). In oneembodiment, the thickness is about 0.02 inches (≈0.508 mm) to about0.040 inches (≈1.02 mm). In one embodiment, the shell thickness is about0.028 inches (≈0.711 mm). In another embodiment, the shell thickness isabout 0.033 inches (≈0.838 mm). In another embodiment, the shellthickness is about 0.038 inches (≈0.965 mm).

In one embodiment described herein, the enteric soft capsule shelldescribed herein, encapsulates a pharmaceutical composition as describedherein. In another embodiment described herein, the enteric soft capsuleshell and encapsulated pharmaceutical composition comprises an outerdimension from about 2 oval to about 30 oval including all iterations ofcapsule sizes within the specified range (e.g., 2 oval, 3 oval, 4 oval,5 oval, 6 oval, 7 oval, 8 oval, 10 oval, 12 oval, 16 oval, 20, or 30oval). In another embodiment described herein, the enteric soft capsuleshell and encapsulated pharmaceutical composition comprises an outerdimension from about 2 round to about 28 round including all iterationsof capsule sizes within the specified range (e.g., 2 round, 3 round, 4round, 5 round, 6 round, 7 round, 8 round, 10 round, 12 round, 16 round,20 round or 28 round). In another embodiment described herein, theenteric soft capsule shell and encapsulated pharmaceutical compositioncomprises an outer dimension from about 2 oblong to about 22 oblongincluding all iterations of capsule sizes within the specified range(e.g., 2 oblong, 3 oblong, 4 oblong, 5 oblong, 6 oblong, 7 oblong, 8oblong, 10 oblong, 11, oblong, 12 oblong, 14 oblong, 16 oblong, 20oblong, or 22 oblong). Dimension specifications of soft capsules andtablets are known to those skilled in the art. See Remington'sEssentials of Pharmaceutics, Pharmaceutical Press Publishing Company,London, UK, 1^(st) Edition, 2013, which is incorporated by referenceherein for such teachings.

In one embodiment, the soft enteric capsules comprising fish oil in thematrix fills described herein are stable for months or years. In oneaspect, the pharmaceutical compositions described herein are stable at25° C. and 60% relative humidity (RH) for about 1 month, about 2 months,about 3 months, about 4 months, about 5 months, about 6 months, about 9months, about 10 months, about 11 months, about 12 months, or evenlonger. In another aspect, the pharmaceutical compositions describedherein are stable for 1 year or longer at 25° C. and 60% RH. In anotheraspect, the pharmaceutical compositions described herein are stable for2 years or longer at 25° C. and 60% RH.

In one embodiment, the pharmaceutical composition described herein isprovided as a dosage kit in a dispensing receptacle. In one aspect, thedispensing receptacle is a moisture proof blister pack, strip pack,aluminum blister, transparent or opaque polymer blister with pouch,polypropylene tubes, colored blister materials, tubes, bottles, andbottles optionally containing a child-resistant feature, optionallycomprising a desiccant, such as a molecular sieve or a silica gel. Inanother aspect, the dosage forms are packaged in a dispensingreceptacle, which may optionally be packaged together in a box or otherenclosure. In another aspect, the dispensing receptacle comprisessufficient amounts of the pharmaceutical composition described herein,for 1 day, 2 days, 6 days, 12 days, 24 days, 30 days, 60 days, or 90days of dosing. In another aspect, the unit dosage form is about 250 mgto about 5000 mg of the pharmaceutical composition comprising an entericsoft capsule and matrix fill as described herein. In another aspect, thedosage kit comprises 1, 2, 6, 12, 24, 30, 60, 90, 120, 150, 180, 240,270, or 300 such enteric soft capsules.

In one embodiment, the pharmaceutical composition described hereinprovides a dosage of a fatty acid composition for administration to asubject. In one embodiment, the fatty acid composition can beadministered to a subject without unpleasant side effects, including butnot limited to, gastric disturbances such as eructation (belching),bloating, and unpleasant fishy after tastes (e.g., “fishy burps”). Thedosage form can be administered, for example, to a subject, or a subjectin need thereof. In one aspect, the subject is a mammal, or a mammal inneed thereof. In one aspect, the subject is a human, or human in needthereof. In one aspect, the human or human in need thereof is a medicalpatient. In one aspect, the human subject can be from ˜0 years of age to99 years of age or older including all iterations of integers within thespecified range. In one aspect, the human subject is a child (˜0-9 yearsold) or an adolescent (˜10-17 years old). In one aspect, the subject isfrom 0 to 9 years of age. In another aspect, the human subject is from10 to 17 years of age. In another aspect, the human subject is over 17years of age. In another aspect, the human subject is an adult (≧18years of age).

In another embodiment, a pharmaceutical composition is administered to asubject in an amount sufficient to provide a therapeutically effectivedose of the fatty acids (e.g., fish oil comprising DHA, EPA, or DPA or acombination thereof) described herein of at least about 1 mg to at leastabout 10,000 mg, at least about 25 mg at least about 5000 mg, at leastabout 50 mg to at least about 3000 mg, at least about 75 mg to at leastabout 2500 mg, or at least about 100 mg to at least about 1000 mg. Inone aspect, the pharmaceutical composition is administered to a subjectand comprises a therapeutically effective dosage amount of the fattyacids (e.g., fish oil comprising DHA, EPA, or DPA) of at least about 50mg, at least about 75 mg, at least about 100 mg, at least about 125 mg,at least about 150 mg, at least about 175 mg, at least about 200 mg, atleast about 225 mg, at least about 250 mg, at least about 275 mg, atleast about 300 mg, at least about 325 mg, at least about 350 mg, atleast about 375 mg, at least about 400 mg, at least about 425 mg, atleast about 450 mg, at least about 475 mg, at least about 500 mg, atleast about 525 mg, at least about 550 mg, at least about 575 mg, atleast about 600 mg, at least about 625 mg, at least about 650 mg, atleast about 675 mg, at least about 700 mg, at least about 725 mg, atleast about 750 mg, at least about 775 mg, at least about 800 mg, atleast about 825 mg, at least about 850 mg, at least about 875 mg, atleast about 900 mg, at least about 925 mg, at least about 950 mg, atleast about 975 mg, at least about 1000 mg, at least about 1025 mg, atleast about 1050 mg, at least about 1075 mg, at least about 1100 mg, atleast about 1125 mg, at least about 1150 mg, at least about 1175 mg, atleast about 1200 mg, at least about 1225 mg, at least about 1250 mg, atleast about 1275 mg, at least about 1300 mg, at least about 1325 mg, atleast about 1350 mg, at least about 1375 mg, at least about 1400 mg, atleast about 1425 mg, at least about 1450 mg, at least about 1475 mg, atleast about, 1500 mg, at least about 1525 mg, at least about 1550 mg, atleast about 1575 mg, at least about 1600 mg, at least about 1625 mg, atleast about 1650 mg, at least about 1675 mg, at least about 1700 mg, atleast about 1725 mg, at least about 1750 mg, at least about 1775 mg, atleast about 1800 mg, at least about 1825 mg, at least about 1850 mg, atleast about 1875 mg, at least about 1900 mg, at least about 1925 mg, atleast about 1950 mg, at least about 1975 mg, at least about 2000 mg, atleast about 2025 mg, at least about 2050 mg, at least about 2075 mg, atleast about 2100 mg, at least about 2125 mg, at least about 2150 mg, atleast about 2175 mg, at least about 2200 mg, at least about 2225 mg, atleast about 2250 mg, at least about 2275 mg, at least about 2300 mg, atleast about 2325 mg, at least about 2350 mg, at least about 2375 mg, atleast about 2400 mg, at least about 2425 mg, at least about 2450 mg, atleast about 2475 mg, at least about 2500 mg, at least about 2525 mg, atleast about 2550 mg, at least about 2575 mg, at least about 2600 mg, atleast about 2625 mg, at least about 2650 mg, at least about 2675 mg, atleast about 2700 mg, at least about 2725 mg, at least about 2750 mg, atleast about 2775 mg, at least about 2800 mg, at least about 2825 mg, atleast about 2850 mg, at least about 2875 mg, at least about 2900 mg, atleast about 2925 mg, at least about 2950 mg, at least about 2975 mg, atleast about 3000 mg, at least about 3025 mg, at least about 3050 mg, atleast about 3075 mg, at least about 3100 mg, at least about 3125 mg, atleast about 3150 mg, at least about 3175 mg, at least about 3200 mg, atleast about 3225 mg, at least about 3250 mg, at least about 3275 mg, atleast about 3300 mg, at least about 3325 mg, at least about 3350 mg, atleast about 3375 mg, at least about 3400 mg, at least about 3425 mg, atleast about 3450 mg, at least about 3475 mg, at least about 3500 mg, atleast about 3525 mg, at least about 3550 mg, at least about 3600 mg, atleast about 3625 mg, at least about 3650 mg, at least about 3675 mg, atleast about 3700 mg, at least about 3725 mg, at least about 3750 mg, atleast about 3775 mg, at least about 3800 mg, at least about 3825 mg, atleast about 3850 mg, at least about 3875 mg, at least about 4000 mg, atleast about 4025 mg, at least about 4050 mg, at least about 4075 mg, atleast about 4100 mg, at least about 4125 mg, at least about 4150 mg, atleast about 4175 mg, at least about 4200 mg, at least about 4225 mg, atleast about 4250 mg, at least about 4275 mg, at least about 4300 mg, atleast about 4325 mg, at least about 4350 mg, at least about 4375 mg, atleast about 4400 mg, at least about 4425 mg, at least about 4450 mg, atleast about 4475 mg, at least about 4500 mg, at least about 4525 mg, atleast about 4550 mg, at least about 4600 mg, at least about 4625 mg, atleast about 4650 mg, at least about 4675 mg, at least about 4700 mg, atleast about 4725 mg, at least about 4750 mg, at least about 4775 mg, atleast about 4800 mg, at least about 4825 mg, at least about 4850 mg, atleast about 4875 mg, or at least about 5000 mg.

In one embodiment, the effective amount of fatty acids administered to apatient or subject in need thereof of is at least about 250 mg perdosage. In another embodiment, the effective amount of fatty acidsadministered to a patient or subject in need thereof is at least about400 mg per dosage. In another embodiment, the effective amount of fattyacids administered to a patient or subject in need thereof is at leastabout 500 mg per dosage. In another embodiment, the effective amount offatty acids administered to a patient or subject in need thereof is atleast about 600 mg per dosage. In another embodiment, the effectiveamount of fatty acids administered to a patient or subject in needthereof is at least about 800 mg per dosage. In another embodiment, theeffective amount of fatty acids administered to a patient or subject inneed thereof is at least about 900 mg per dosage. In another embodiment,the effective amount of fatty acids administered to a patient or subjectin need thereof is at least about 1000 mg per dosage. In anotherembodiment, the effective amount of fatty acids administered to apatient or subject in need thereof is at least about 1200 mg per dosage.In another embodiment, the effective amount of fatty acids administeredto a patient or subject in need thereof is at least about 1400 mg perdosage. In another embodiment, the effective amount of fatty acidsadministered to a patient or subject in need thereof is at least about2000 mg per dosage. In another embodiment, the effective amount of fattyacids administered to a patient or subject in need thereof is at leastabout 3000 mg per dosage. In another embodiment, the effective amount offatty acids administered to a patient or subject in need thereof is atleast about 4000 mg per dosage.

In one embodiment, the pharmaceutical composition is administered in anamount of at least about 250 mg per day. In one embodiment, thepharmaceutical composition is administered in an amount of at leastabout 500 mg per day. In one embodiment, the pharmaceutical compositionis administered in an amount of at least about 1000 mg per day. Inanother embodiment, the pharmaceutical composition is administered in anamount of at least about 2000 mg per day. In another embodiment, thepharmaceutical composition is administered in an amount of at leastabout 3000 mg per day. In another embodiment, the pharmaceuticalcomposition is administered in an amount of at least about 4000 mg perday. In another embodiment, the pharmaceutical composition isadministered in an amount of at least about 5000 mg per day.

In one embodiment, the pharmaceutical composition is administered daily.In another embodiment, the pharmaceutical composition is administeredevery other day. In another embodiment, the daily dosage ofpharmaceutical composition is administered in a single daily dose. Inanother embodiment, the pharmaceutical composition is administered individed doses, with the daily dose divided into two administrations,three administrations, or four administrations per day. The dosage formcan be administered, for example, 1×, 2×, 3×, 4×, 5×, 6×, or even moretimes per day. One or more dosage form can be administered, for example,for 1, 2, 3, 4, 5, 6, 7 days, or even longer. One or more dosage formscan be administered, for example, for 1, 2, 3, 4 weeks, or even longer.One or more dosage forms can be administered, for example, for 1, 2, 3,4, 5, 6, 7, 8, 9, 10, 11, 12 months, 1 year, 2, years, 3 years, 4 years,5 years, over 5 years, a decade, multiple decades, or even longer. Oneor more dosage forms can be administered at a regular interval until thesubject or subject in need thereof, does not require treatment,prophylaxis, or amelioration of any disease or condition including butnot limited to hyperdyslipidemia or a cardiovascular-related disease.

In one embodiment, the pharmaceutical composition is administered withfood. In another embodiment, the pharmaceutical composition isadministered with a low fat meal. In another embodiment, thepharmaceutical composition is administered without food. In anotherembodiment, the pharmaceutical composition is administered in thefasting state.

In one embodiment, the administration of the pharmaceutical compositiondescribed herein depends on the physician, dose, and patient in need oftreatment thereof. See, LOVAZA® (omega-3 acid ethyl esters) capsules,for oral use prescribing information, GlaxoSmithKline (2013); VASCEPA®(icosapent ethyl) capsules, for oral use prescribing information, AmarinPharma Inc. (2013); and EPANOVA® (omega-3 carboxylic acids) capsules,for oral use prescribing information AstraZeneca Pharmaceuticals (2014);each of which is incorporated herein for the specific teachings thereof.

In another embodiment, the pharmaceutical composition described hereinfurther comprises one or more non-steroidal anti-inflammatory drugs(NSAIDS). The NSAID may be co-administered, administered separately, orcombined in the dosage form. See, e.g., WO 2013/155430, which isincorporated by reference herein for such teachings. The NSAID can beadministered about 30 minutes before taking a dosage form describedherein.

In another embodiment, the active ingredient comprises a fatty acid orderivatives thereof, combined with aspirin, ibuprofen, naproxene,diclofenac, ketoprofen, celecoxib, other non-steroidal anti-inflamatoryactive drugs (NSAIDs), or combinations thereof. In one embodiment, thepharmaceutical composition comprises a PUFA combined with aspirin.

In another embodiment, the pharmaceutical composition described hereinfurther comprises one or more statins (HMG-CoA reductase inhibitors)comprising atorvastatin, lovastatin, simvastatin, pravastatin,rosuvastatin, fluvastatin, pitavastatin, himastatin, or combinationsthereof. The statin may be co-administered, administered separately, orcombined in the dosage form.

In another embodiment, the pharmaceutical composition described hereinfurther comprises one or more cardiovascular drugs, including ACEinhibitors, aldosterone inhibitors, angiotensin II receptor blockers,beta-blockers, calcium channel blockers, or combinations thereof. Thecardiovascular drugs may be co-administered, administered separately, orcombined in the dosage form.

One embodiment described herein is a method for treating, retarding theprogression of, delaying the onset of, prophylaxis of, amelioration of,or reducing the symptoms of a disease related to hyperdyslipidemia usinga pharmaceutical composition as described herein. Another embodimentdescribed herein is a method for treating, retarding the progression of,delaying the onset of, prophylaxis of, amelioration of, or reducing thesymptoms of a cardiovascular-related disease using a pharmaceuticalcomposition as described herein. See U.S. Patent Application PublicationNo. US 2010/0278879, which is incorporated by reference herein for itsspecific teachings of treating cardiovascular-related diseases. The term“cardiovascular-related disease” as used herein refers to any disease ordisorder of the heart or blood vessels (i.e., arteries and veins) or anysymptom thereof. The term “cardiovascular-related disease” as usedherein also refers any disease or condition that causes or contributesto a “cardiovascular disease.” Non-limiting examples of“cardiovascular-related diseases” include acute cardiac ischemic events,acute myocardial infarction, angina, angina pectoris, arrhythmia, atrialfibrillation, atherosclerosis, arterial fibrillation, cardiacinsufficiency, cardiovascular disease, chronic heart failure, chronicstable angina, congestive heart failure, coronary artery disease,coronary heart disease, deep vein thrombosis, diabetes, diabetesmellitus, diabetic neuropathy, diastolic dysfunction in subjects withdiabetes mellitus, edema, essential hypertension, eventual pulmonaryembolism, fatty liver disease, heart disease, heart failure, homozygousfamilial hypercholesterolemia (HoFH), homozygous familialsitosterolemia, hypercholesterolemia, hyperlipidemia, hyperlipidemia inHIV positive subjects, hypertension, hypertriglyceridemia, ischemiccomplications in unstable angina and myocardial infarction, low bloodpressure, metabolic syndrome, mixed dyslipidemia, moderate to mild heartfailure, myocardial infarction, obesity management, paroxysmalatrial/arterial fibrillation/fibrillation/flutter, paroxysmalsupraventricular tachycardias (PSVT), particularly severe or rapid onsetedema, platelet aggregation, primary hypercholesterolemia, primaryhyperlipidemia, pulmonary arterial hypertension, pulmonary hypertension,recurrent hemodynamically unstable ventricular tachycardia (VT),recurrent ventricular arrhythmias, recurrent ventricular fibrillation(VF), ruptured aneurysm, sitosterolemia, stroke, supraventriculartachycardia, symptomatic atrial fibrillation/flutter, tachycardia, typeII diabetes, vascular disease, venous thromboembolism, ventriculararrhythmias, and other cardiovascular events. The term “treatment” asused herein in relation a given disease or disorder, includes, but isnot limited to, inhibiting the disease or disorder, for example,arresting the development of the disease or disorder; relieving thedisease or disorder, for example, causing regression of the disease ordisorder; or relieving a condition caused by or resulting from thedisease or disorder, for example, relieving, preventing or treatingsymptoms of the disease or disorder. The term “prevention” in relationto a given disease or disorder means: preventing the onset of diseasedevelopment if none had occurred, preventing the disease or disorderfrom occurring in a subject that may be predisposed to the disorder ordisease but has not yet been diagnosed as having the disorder ordisease, and/or preventing further disease/disorder development ifalready present.

In another embodiment, the pharmaceutical composition is suitable forthe treatment, prevention, amelioration of a plurality of diseases andsymptoms comprising high blood pressure, cancer, rheumatoid arthritis,menstrual pain (dysmenorrhea), attention deficit-hyperactivity disorder(ADHD) in children, attention deficit-hyperactivity disorder (ADHD) inadults, Raynaud's syndrome, stroke, weak bones (e.g., osteoporosis),hardening of the arteries (e.g., atherosclerosis), kidney problems,bipolar disorder, psychosis, weight loss, endometrial cancer,age-related eye disease (age-related macular degeneration, amd),reducing the risk of blood vessel re-blockage after heart bypass surgeryor “balloon” catheterization (e.g., balloon angioplasty), recurrentmiscarriage in pregnant women with antiphospholipid syndrome, kidneyproblems following heart transplant, kidney damage followingcyclosporine therapy, movement disorder in children (e.g., dyspraxia),developmental coordination disorder, preventing blockage of grafts usedin kidney dialysis, psoriasis, high cholesterol, recovery after coronaryartery bypass surgery, cancer-related weight loss, asthma, allergies,Alzheimer's disease, atopic dermatitis, atrial fibrillation, depression,dry eye syndrome, cataracts, chronic fatigue syndrome (CFS), chronickidney disease, reduced thinking skills (e.g., cognitive function),Crohn's disease, prediabetes, infant development, ulcerative colitis,pregnancy complications, salicylate intolerance, schizophrenia, systemiclupus erythematosus (SLE), irregular heartbeat affecting the ventricles(ventricular arrhythmias), improving night vision in children withdyslexia or a combination of disease symptoms described herein.

In another embodiment, the pharmaceutical composition is suitable forthe treatment, prevention, amelioration of a cardiovascular-relateddisease comprising hyperlipidemia, hypertriglyceridemia, hypertension,hypercholesterolemia, mixed dyslipidemia, sitosterolemia,atherosclerosis, transient ischemic attack, systolic dysfunction,diastolic dysfunction, aneurysm, aortic dissection, myocardial ischemia,acute myocardial infarction (AMI), acute ST-segment elevation myocardialinfarction (STEMI), acute non-ST-segment elevation myocardial infarction(NSTEMI), ventricular arrhythmias, angina pectoris, unstable angina(UA), and stable angina (SA), myocardial infarction, congestive heartfailure, dilated congestive cardiomyopathy, hypertrophic cardiomyopathy,restrictive cardiomyopathy, cor pulmonale, arrhythmia, valvular heartdisease, endocarditis, pulmonary embolism, venous thrombosis, peripheralvascular disease, and peripheral artery disease, rheumatoid arthritis,dysmenorrhea, attention deficit-hyperactivity disorder in children,attention deficit-hyperactivity disorder in adults, Raynaud's syndrome,stroke, osteoporosis, kidney problems, bipolar disorder, psychosis,weight loss, endometrial cancer, macular degeneration, kidney damage,dyspraxia, developmental coordination disorder, psoriasis, asthma,allergies, Alzheimer's disease, atopic dermatitis, atrial fibrillation,depression, dry eye syndrome, cataracts, chronic fatigue syndrome (CFS),chronic kidney disease, Crohn's disease, prediabetes, ulcerativecolitis, salicylate intolerance, schizophrenia, systemic lupuserythematosus (SLE), or a combination thereof.

In one embodiment described herein, for the treatment ofcardiovascular-related diseases (e.g., hyperlipidemia,hypertriglyceridemia, hypertension, hypercholesterolemia, mixeddyslipidemia, inter alia), the dosage form administered to the subjector subject in need thereof may comprise a fatty acid as the only activeingredient or in combination with one or more non-steroidalanti-inflammatory drugs (e.g., aspirin, ibuprofen, naproxen, ketoprofen,celecoxib, or combinations thereof), statins (e.g., atorvastatin,lovastatin, simvastatin, pravastatin, rosuvastatin, fluvastatin,pitavastatin, himastatin, or combinations thereof), or cardiovasculardrugs (e.g., ACE inhibitors, aldosterone inhibitors, angiotensin IIreceptor blockers, beta-blockers, calcium channel blockers, orcombinations thereof).

One embodiment described herein is a method of blood lipid therapycomprising administering to a subject or subject group in need thereofthe pharmaceutical composition as described herein. In one aspect, thesubject may be a mammal, or a mammal in need thereof. In one aspect, thedosage form can be administered, for example, to a human or a human inneed thereof. In one aspect, the human subject or a human subject inneed thereof is a medical patient. In another embodiment, the subject orsubject group has hypertriglyceridemia, hypercholesterolemia, mixeddyslipidemia, very high triglycerides, or a mixture thereof.

In another embodiment, the subject or subject group being treated has abaseline triglyceride level (or median baseline triglyceride level inthe case of a subject group), fed or fasting, of at least about 200mg/dL, at least about 300 mg/dL, at least about 400 mg/dL, at leastabout 500 mg/dL, at least about 600 mg/dL, at least about 700 mg/dL, atleast about 800 mg/dL, at least about 900 mg/dL, at least about 1000mg/dL, at least about 1100 mg/dL, at least about 1200 mg/dL, at leastabout 1300 mg/dL, at least about 1400 mg/dL, at least about 1500 mg/dL,at least about 1600 mg/dL, at least about 1700 mg/dL, at least about1800 mg/dL, at least about 1900 mg/dL, at least about 2000 mg/dL, atleast about 2100 mg/dL, at least about 2200 mg/dL, at least about 2300mg/dL, at least about 2400 mg/dL, or at least about 2500 mg/dL.

In another embodiment, the subject's (or subject group's mean) baselinelipid profile is measured prior to initiating therapy. In anotherembodiment, subjects or a subject group comprising a baseline non-HDL-Cvalue of about 200 mg/dL to about 400 mg/dL, for example at least about210 mg/dL, at least about 220 mg/dL, at least about 230 mg/dL, at leastabout 240 mg/dL, at least about 250 mg/dL, at least about 260 mg/dL, atleast about 270 mg/dL, at least about 280 mg/dL, at least about 290mg/dL, or at least about 300 mg/dL; baseline total cholesterol value ofabout 250 mg/dL to about 400 mg/dL, for example at least about 260mg/dL, at least about 270 mg/dL, at least about 280 mg/dL or at leastabout 290 mg/dL; baseline vLDL-C value of about 140 mg/dL to about 200mg/dL, for example at least about 150 mg/dL, at least about 160 mg/dL,at least about 170 mg/dL, at least about 180 mg/dL or at least about 190mg/dL; baseline HDL-C value of about 10 mg/dL to about 60 mg/dL, forexample not more than about 40 mg/dL, not more than about 35 mg/dL, notmore than about 30 mg/dL, not more than about 25 mg/dL, not more thanabout 20 mg/dL, or not more than about 15 mg/dL; and/or baseline LDL-Cvalue of about 50 mg/dL to about 300 mg/dL, for example not less thanabout 100 mg/dL, not less than about 90 mg/dL, not less than about 80mg/dL, not less than about 70 mg/dL, not less than about 60 mg/dL or notless than about 50 mg/dL.

In one embodiment, upon treatment of a subject or subject group in needthereof with the pharmaceutical composition described herein over aperiod of about 1 week to about 200 weeks, about 1 week to about 100weeks, about 1 week to about 80 weeks, about 1 week to about 50 weeks,about 1 week to about 40 weeks, about 1 week to about 20 weeks, about 1week to about 15 weeks, about 1 week to about 12 weeks, about 1 week toabout 10 weeks, about 1 week to about 5 weeks, about 1 week to about 2weeks or about 1 week, the subject or subject group exhibits one or moreoutcomes comprising reduced triglyceride levels compared to baselinemeasurements, reduced Apo B levels compared to baseline measurements,increased HDL-C levels compared to baseline measurements, no increase inLDL-C levels compared to baseline measurements, a reduction in LDL-Clevels compared to baseline measurements, a reduction in non-HDL-Clevels compared to baseline measurements, a reduction in vLDL levelscompared to baseline measurements, an increase in apo A-I levelscompared to baseline measurements, an increase in apo A-I/apo B ratiocompared to baseline measurements, a reduction in lipoprotein A levelscompared to baseline measurements, a reduction in LDL particle numbercompared to baseline measurements, an increase in mean LDL size comparedto baseline measurements, a reduction in remnant-like particlecholesterol compared to baseline measurements, a reduction in oxidizedLDL compared to baseline measurements, no change or a reduction infasting plasma glucose (FPG) compared to baseline measurements, areduction in hemoglobin A, (HbA) compared to baseline measurements, areduction in homeostasis model insulin resistance compared to baselinemeasurements, a reduction in lipoprotein associated phospholipase A2compared to baseline measurements, a reduction in Intracellular AdhesionMolecule 1 compared to baseline measurements, a reduction inInterleukin-6 compared to baseline measurements, a reduction inPlasminogen Activator Inhibitor 1 compared to baseline measurements, areduction in high sensitivity C-reactive protein (hsCRP) compared tobaseline measurements, an increase in serum phospholipid EPA compared tobaseline measurements, an increase in red blood cell membrane EPAcompared to baseline measurements, or any mixture of outcomes thereof.

In another embodiment, upon treatment with the pharmaceuticalcomposition described herein, the subject or subject group exhibits anoutcome comprising, a reduction in triglyceride levels of at least about5%, at least about 10%, at least about 15%, at least about 20%, at leastabout 25%, at least about 30%, at least about 35%, at least about 40%,at least about 45%, at least about 50%, at least about 55% or at leastabout 75% (actual % change or median % change) as compared to baselinemeasurements.

In another embodiment, upon treatment with the pharmaceuticalcomposition described herein, the subject or subject group exhibits anoutcome comprising a less than 30% increase, less than 20% increase,less than 10% increase, less than 5% increase or no increase innon-HDL-C levels, or a reduction in non-HDL-C levels of at least about1%, at least about 3%, at least about 5%, at least about 10%, at leastabout 15%, at least about 20%, at least about 25%, at least about 30%,at least about 35%, at least about 40%, at least about 45%, at leastabout 50%, at least about 55%, at least about 60%, at least about 65%,at least about 70%, or at least about 75% (actual % change or median %change) as compared to baseline measurements; or substantially nochange, no change or an increase in HDL-C levels of at least about 5%,at least about 10%, at least about 15%, at least about 20%, at leastabout 25%, at least about 30%, at least about 35%, at least about 40%,at least about 45%, at least about 50%, at least about 55%, at leastabout 60%, at least about 65%, at least about 70%, or at least about 75%(actual % change or median % change) as compared to baselinemeasurements; or a less than 60% increase, less than 50% increase, lessthan 40% increase, less than 30% increase, less than 20% increase, lessthan 10% increase, less than 5% increase or no increase in LDL-C levelsor a reduction in LDL-C levels of at least about 5%, at least about 10%,at least about 15%, at least about 20%, at least about 25%, at leastabout 30%, at least about 35%, at least about 40%, at least about 45%,at least about 50%, at least about 55%, at least about 60%, at leastabout 65%, at least about 70%, or at least about 75% (actual % change ormedian % change) as compared to baseline measurements or a decrease inApo B levels of at least about 5%, at least about 10%, at least about15%, at least about 20%, at least about 25%, at least about 30%, atleast about 35%, at least about 40%, at least about 45%, at least about50%, at least about 55%, at least about 60%, at least about 65%, atleast about 70%, or at least about 75% (actual % change or median %change) as compared to baseline measurements or a reduction in vLDLlevels of at least about 5%, at least about 10%, at least about 15%, atleast about 20%, at least about 25%, at least about 30%, at least about35%, at least about 40%, at least about 45%, at least about 50%, atleast about 55%, at least about 60%, at least about 65%, at least about70%, at least about 75%, at least about 80%, at least about 85%, atleast about 90%, at least about 95%, or at least about 100% (actual %change or median % change) compared to baseline measurements or anincrease in apo A-I levels of at least about 5%, at least about 10%, atleast about 15%, at least about 20%, at least about 25%, at least about30%, at least about 35%, at least about 40%, at least about 45%, atleast about 50%, at least about 55%, at least about 60%, at least about65%, at least about 70%, at least about 75%, at least about 80%, atleast about 85%, at least about 90%, at least about 95%, or at leastabout 100% (actual % change or median % change) compared to baselinemeasurements; or an increase in apo A-I/apo B ratio of at least about5%, at least about 10%, at least about 15%, at least about 20%, at leastabout 25%, at least about 30%, at least about 35%, at least about 40%,at least about 45%, at least about 50%, at least about 55%, at leastabout 60%, at least about 65%, at least about 70%, at least about 75%,at least about 80%, at least about 85%, at least about 90%, at leastabout 95%, or at least about 100% (actual % change or median % change)compared to baseline measurements; or a reduction in lipoprotein(a)levels of at least about 5%, at least about 10%, at least about 15%, atleast about 20%, at least about 25%, at least about 30%, at least about35%, at least about 40%, at least about 45%, at least about 50%, atleast about 55%, at least about 60%, at least about 65%, at least about70%, at least about 75%, at least about 80%, at least about 85%, atleast about 90%, at least about 95%, or at least about 100% (actual %change or median % change) compared to baseline measurements; or areduction in mean LDL particle number of at least about 5%, at leastabout 10%, at least about 15%, at least about 20%, at least about 25%,at least about 30%, at least about 35%, at least about 40%, at leastabout 45%, at least about 50%, at least about 55%, at least about 60%,at least about 65%, at least about 70%, at least about 75%, at leastabout 80%, at least about 85%, at least about 90%, at least about 95%,or at least about 100% (actual % change or median % change) compared tobaseline measurements; or an increase in mean LDL particle size of atleast about 5%, at least about 10%, at least about 15%, at least about20%, at least about 25%, at least about 30%, at least about 35%, atleast about 40%, at least about 45%, at least about 50%, at least about55%, at least about 60%, at least about 65%, at least about 70%, atleast about 75%, at least about 80%, at least about 85%, at least about90%, at least about 95%, or at least about 100% (actual % change ormedian % change) compared to baseline measurements; or a reduction inremnant-like particle cholesterol of at least about 5%, at least about10%, at least about 15%, at least about 20%, at least about 25%, atleast about 30%, at least about 35%, at least about 40%, at least about45%, at least about 50%, at least about 55%, at least about 60%, atleast about 65%, at least about 70%, at least about 75%, at least about80%, at least about 85%, at least about 90%, at least about 95%, or atleast about 100% (actual % change or median % change) compared tobaseline measurements; or a reduction in oxidized LDL of at least about5%, at least about 10%, at least about 15%, at least about 20%, at leastabout 25%, at least about 30%, at least about 35%, at least about 40%,at least about 45%, at least about 50%, at least about 55%, at leastabout 60%, at least about 65%, at least about 70%, at least about 75%,at least about 80%, at least about 85%, at least about 90%, at leastabout 95%, or at least about 100% (actual % change or median % change)compared to baseline measurements; or substantially no change, no changeor a reduction in fasting plasma glucose (FPG) of at least about 5%, atleast about 10%, at least about 15%, at least about 20%, at least about25%, at least about 30%, at least about 35%, at least about 40%, atleast about 45%, at least about 50%, at least about 55%, at least about60%, at least about 65%, at least about 70%, at least about 75%, atleast about 80%, at least about 85%, at least about 90%, at least about95%, or at least about 100% (actual % change or median % change)compared to baseline measurements; or substantially no change, no changeor a reduction in hemoglobin A (HbA) of at least about 5%, at leastabout 10%, at least about 15%, at least about 20%, at least about 25%,at least about 30%, at least about 35%, at least about 40%, at leastabout 45%, or at least about 50% (actual % change or median % change)compared to baseline or a placebo arm or a reduction in homeostasismodel index insulin resistance of at least about 5%, at least about 10%,at least about 15%, at least about 20%, at least about 25%, at leastabout 30%, at least about 35%, at least about 40%, at least about 45%,at least about 50%, at least about 55%, at least about 60%, at leastabout 65%, at least about 70%, at least about 75%, at least about 80%,at least about 85%, at least about 90%, at least about 95%, or at leastabout 100% (actual % change or median % change) compared to baseline ora placebo arm; or a reduction in Lipoprotein Associated Phospholipase A2of at least about 5%, at least about 10%, at least about 15%, at leastabout 20%, at least about 25%, at least about 30%, at least about 35%,at least about 40%, at least about 45%, at least about 50%, at leastabout 55%, at least about 60%, at least about 65%, at least about 70%,at least about 75%, at least about 80%, at least about 85%, at leastabout 90%, at least about 95%, or at least about 100% (actual % changeor median % change) compared to baseline measurements; or a reduction inIntracellular Adhesion Molecule-1 of at least about 5%, at least about10%, at least about 15%, at least about 20%, at least about 25%, atleast about 30%, at least about 35%, at least about 40%, at least about45%, at least about 50%, at least about 55%, at least about 60%, atleast about 65%, at least about 70%, at least about 75%, at least about80%, at least about 85%, at least about 90%, at least about 95%, or atleast about 100% (actual % change or median % change) compared tobaseline measurements; or a reduction in Interleukin-6 of at least about5%, at least about 10%, at least about 15%, at least about 20%, at leastabout 25%, at least about 30%, at least about 35%, at least about 40%,at least about 45%, at least about 50%, at least about 60%, at leastabout 65%, at least about 70%, at least about 75%, at least about 80%,at least about 85%, at least about 90%, at least about 95%, or at leastabout 100% (actual % change or median % change) compared to baselinemeasurements; or a reduction in Plasminogen Activator Inhibitor 1 of atleast about 5%, at least about 10%, at least about 15%, at least about20%, at least about 25%, at least about 30%, at least about 35%, atleast about 40%, at least about 45%, at least about 50%, at least about55%, at least about 60%, at least about 65%, at least about 70%, atleast about 75%, at least about 80%, at least about 85%, at least about90%, at least about 95%, or at least about 100% (actual % change ormedian % change) compared to baseline; or a reduction in highsensitivity C-reactive protein (hsCRP) of at least about 5%, at leastabout 10%, at least about 15%, at least about 20%, at least about 25%,at least about 30%, at least about 35%, at least about 40%, at leastabout 45%, at least about 50%, at least about 55%, at least about 60%,at least about 65%, at least about 70%, at least about 75%, at leastabout 80%, at least about 85%, at least about 90%, at least about 95%,or at least about 100% (actual % change or median % change) compared tobaseline measurements; or an increase in serum, plasma and/or RBC EPA ofat least about 5%, at least about 10%, at least about 15%, at leastabout 20%, at least about 25%, at least about 30%, at least about 35%,at least about 40%, at least about 45%, at least about 50%, at leastabout 55%, at least about 60%, at least about 65%, at least about 70%,at least about 75%, at least about 80%, at least about 85%, at leastabout 90%, at least about 95%, at least about 100%, at least about 200%or at least about 400% (actual % change or median % change) compared tobaseline measurements; or an increase in serum phospholipid and/or redblood cell membrane EPA of at least about 5%, at least about 10%, atleast about 15%, at least about 20%, at least about 25%, at least about30%, at least about 35%, at least about 40%, at least about 45%, atleast about 50%, at least about 55%, at least about 60%, at least about65%, at least about 70%, at least about 75%, at least about 80%, atleast about 85%, at least about 90%, at least about 95%, at least about100%, at least about 200%, or at least about 400% (actual % change ormedian % change) compared to baseline measurements; or a reduction orincrease in one or more of serum phospholipid and/or red blood cell DHA,DPA, AA, PA or OA of at least about 5%, at least about 10%, at leastabout 15%, at least about 20%, at least about 25%, at least about 30%,at least about 35%, at least about 40%, at least about 45%, at leastabout 50%, at least about 55%, at least about 60%, at least about 65%,or at least about 75% (actual % change or median % change) compared tobaseline measurements; or a reduction in total cholesterol of at leastabout 5%, at least about 10%, at least about 15%, at least about 20%, atleast about 25%, at least about 30%, at least about 35%, at least about40%, at least about 45%, at least about 50%, at least about 55%, atleast about 60%, at least about 65%, or at least about 75% (actual %change or median % change) compared to baseline measurements or anycombination of outcomes thereof.

The listed parameters immediately above can be measured in accordancewith any clinically acceptable methodology. For example, triglycerides,total cholesterol, HDL-C, and fasting blood sugar can be sample fromserum and analyzed using standard photometry techniques. VLDL-TG, LDL-C,and VLDL-C can be calculated or determined using serum lipoproteinfractionation by preparative ultracentrifugation and subsequentquantitative analysis by refractometry or by analytic ultracentrifugalmethodology. Apo A1, Apo B and hsCRP can be determined from serum usingstandard nephelometry techniques. Lipoprotein (a) can be determined fromserum using standard turbidimetric immunoassay techniques. LDL particlenumber and particle size can be determined using nuclear magneticresonance (NMR) spectrometry. Remnants of lipoproteins andLDL-Phospholipase A2 can be determined from EDTA plasma or serum andserum, respectively, using enzymatic immunoseparation techniques.Oxidized LDL, Intercellular Adhesion Molecule-1 and Interleukin-2 levelscan be determined from serum using standard enzyme immunoassaytechniques known in the art.

In one embodiment, the pharmaceutical composition is administered in anamount and for a duration effective to reduce serum or plasmatriglyceride levels by at least about 50 mg/dL to at least about 1000mg/dL. In one aspect, the pharmaceutical composition is administered inan amount and for a duration effective to reduce serum or plasmatriglyceride levels by at least about 50 mg/dL, at least about 60 mg/dL,at least about 70 mg/dL, at least about 80 mg/dL, at least about 90mg/dL, at least about 100 mg/dL. In another aspect, the pharmaceuticalcomposition is administered in an amount and for a duration effective toreduce serum or plasma triglyceride levels by at least about 110 mg/dL,at least about 120 mg/dL, at least about 130 mg/dL, at least about 140mg/dL, or at least about 150 mg/dL. In another aspect, thepharmaceutical composition is administered in an amount and for aduration effective to reduce serum or plasma triglyceride levels by atleast about 160 mg/dL, at least about 170 mg/dL, at least about 180mg/dL, at least about 190 mg/dL, or at least about 200 mg/dL. In anotheraspect, the pharmaceutical composition is administered in an amount andfor a duration effective to reduce serum or plasma triglyceride levelsby at least about 210 mg/dL, at least about 220 mg/dL, at least about230 mg/dL, at least about at least about 240 mg/dL, or at least about250 mg/dL. In another aspect, the pharmaceutical composition isadministered in an amount and for a duration effective to reduce serumor plasma triglyceride levels by at least about 260 mg/dL, 270 mg/dL, atleast about 280 mg/dL, at least about 290 mg/dL, or at least about 300mg/dL. In another aspect, the pharmaceutical composition is administeredin an amount and for a duration effective to reduce serum or plasmatriglyceride levels by at least about 350 mg/dL, at least about 400mg/dL, at least about 450 mg/dL, or at least about 500 mg/dL. In anotheraspect, the pharmaceutical composition is administered in an amount andfor a duration effective to reduce serum or plasma triglyceride levelsby at least about 600 mg/dL, at least about 700 mg/dL, at least about800 mg/dL, at least about 900 mg/dL, or at least about 1000 mg/dL.

In one embodiment, the pharmaceutical composition is administered in anamount and for a duration effective to reduce serum or plasmatriglyceride levels to an amount less than about 1000 mg/dL. In anotherembodiment, the pharmaceutical composition is administered in an amountand for a duration effective to reduce serum or plasma triglyceridelevels to an amount less than about 900 mg/dL. In another embodiment,the pharmaceutical composition is administered in an amount and for aduration effective to reduce serum or plasma triglyceride levels to anamount less than about 800 mg/dL. In another embodiment, thepharmaceutical composition is administered in an amount and for aduration effective to reduce serum or plasma triglyceride levels to anamount less than about 700 mg/dL. In another embodiment, thepharmaceutical composition is administered in an amount and for aduration effective to reduce serum or plasma triglyceride levels to anamount less than about 600 mg/dL. In another embodiment, thepharmaceutical composition is administered in an amount and for aduration effective to reduce serum or plasma triglyceride levels to anamount less than about 500 mg/dL. In another embodiment, thepharmaceutical composition is administered in an amount and for aduration effective to reduce serum or plasma triglyceride levels to anamount less than about 400 mg/dL. In another embodiment, thepharmaceutical composition is administered in an amount and for aduration effective to reduce serum or plasma triglyceride levels to anamount less than about 350 mg/dL. In another embodiment, thepharmaceutical composition is administered in an amount and for aduration effective to reduce serum or plasma triglyceride levels to anamount less than about 300 mg/dL. In another embodiment, thepharmaceutical composition is administered in an amount and for aduration effective to reduce serum or plasma triglyceride levels to anamount less than about 200 mg/dL. In another embodiment, thepharmaceutical composition is administered in an amount and for aduration effective to reduce serum or plasma triglyceride levels to anamount less than about 150 mg/dL. In another embodiment, thepharmaceutical composition is administered in an amount and for aduration effective to reduce serum or plasma triglyceride levels to anamount less than about 120 mg/dL.

In another embodiment, methods of treating or preventing risk ofrecurrent nonfatal myocardial infarction in a patient with a history ofmyocardial infarction comprise administering to the patient one or morepharmaceutical compositions as disclosed herein.

In another embodiment, methods of slowing progression of or promotingregression of atherosclerotic disease in a patient in need thereof,comprise administering to a subject in need thereof one or morepharmaceutical compositions as disclosed herein.

In another embodiment, methods of treating or preventing very high serumtriglyceride levels (e.g., Types IV and V hyperlipidemia) in a patientin need thereof, comprise administering to the patient one or morepharmaceutical compositions as disclosed herein.

In another embodiment, methods of treating subjects having very highserum triglyceride levels (e.g., greater than 1000 mg/dL or greater than2000 mg/dL) and that are at risk of developing pancreatitis, compriseadministering to the patient one or more pharmaceutical compositions asdisclosed herein.

In one embodiment, the pharmaceutical composition is administered in anamount and for a duration effective to increase plasma EPA levels by atleast 100% above pre-treatment levels. In another embodiment, thepharmaceutical composition is administered in an amount and for aduration effective to increase plasma EPA levels by at least about 200%,at least about 250%, at least about 300%, at least about 350%, at leastabout 400%, at least about 450%, at least about 500%, at least about750%, at least about 1000%, at least about 1500%, or at least about2000% above pre-treatment levels. In another embodiment, thepharmaceutical composition is administered for a time and in an amounteffective to increase plasma EPA levels by at least about 2000% abovepre-treatment levels.

In one embodiment, the pharmaceutical composition is administered in anamount and for a duration effective to increase plasma DHA levels by atleast about 50% above pre-treatment levels. In another embodiment, thepharmaceutical composition is administered in an amount and for aduration effective to increase plasma DHA levels by at least about 55%,at least about 60%, at least about 65%, at least about 70%, at leastabout 75%, at least about 80%, at least about 85%, or at least about 90%above pre-treatment levels.

In one embodiment, the pharmaceutical composition is administered in anamount and for a duration effective to increase plasma DPA levels by atleast about 50% above pre-treatment levels. In another embodiment, thepharmaceutical composition is administered in an amount and for aduration effective to increase plasma DPA levels by at least about 55%,at least about 60%, at least about 65%, at least about 70%, at leastabout 75%, at least about 80%, at least about 85%, at least about 90%,at least about 95%, or at least about 100% above pre-treatment levels.In another embodiment, the pharmaceutical composition is administered inan amount and for a duration effective to increase plasma DPA levels byat least about 110%, at least about 120%, or at least about 125% abovepre-treatment levels.

In one embodiment, the pharmaceutical composition is administered in anamount and for a duration effective to reduce arachidonic acid (AA)concentration in plasma by at least about 5% below pre-treatment levels.In another embodiment, the pharmaceutical composition is administered inan amount and for a duration effective to reduce arachidonic (AA)concentration in plasma by at least about 6%, at least about 7%, atleast about 8%, at least about 9%, at least about 10%, at least about11%, at least about 12%, at least about 13%, at least about 14%, atleast about 15%, at least about 16%, at least about 17%, at least about18%, at least about 19%, at least about 20%, at least about 21%, atleast about 22%, at least about 23%, at least about 24%, or at leastabout 25% below pre-treatment levels.

In one embodiment, the pharmaceutical composition is administered in anamount and for a duration effective to reduce plasma arachidonic acidconcentration by at least about 25 μg/mL. In another embodiment, thepharmaceutical composition is administered in an amount and for aduration sufficient to reduce plasma AA levels by at least about 50μg/mL, at least about 55 μg/mL, at least about 60 μg/mL, at least about65 μg/mL, at least about 70 μg/mL, at least about 75 μg/mL, at leastabout 80 μg/mL, at least about at least about 85 μg/mL, at least about90 μg/mL, at least about 95 μg/mL or at least about 100 μg/mL.

Methods are also provided for increasing the EPA:AA ratio, withoutregard to the patient's pretreatment plasma triglyceride levels. Themethods comprise administering the pharmaceutical composition describedherein, to a patient having an EPA:AA ratio below at least about 0.25,in an amount and for a duration sufficient to increase the patient'sEPA:AA ratio to at least about 0.25. In one embodiment, thepharmaceutical composition is administered in an amount and for aduration sufficient to increase the patient's EPA:AA ratio to at leastabout 0.3, at least about 0.35, at least about 0.40, at least about0.45, at least about 0.50, at least about 0.55, at least about 0.60, atleast about 0.61, at least about 0.62, at least about 0.63, at leastabout 0.64, or at least about 0.65.

In one embodiment, the pharmaceutical composition is administered in anamount, and for a duration, effective to reduce plasma arachidonic acidconcentration by at least about 25 pg/mL. In another embodiment, thepharmaceutical composition is administered in an amount and for aduration sufficient to reduce plasma AA levels by at least about 50pg/mL, at least about 55 pg/mL, at least about 60 pg/mL, at least about65 pg/mL, at least about 70 pg/mL, at least about 75 pg/mL, at leastabout 80 pg/mL, at least about 85 pg/mL, at least about 90 pg/mL, atleast about 95 pg/mL or at least about 100 pg/mL.

Methods are also provided for increasing a patient's serum or plasmaApoCIII levels, without regard to the patient's pretreatment plasmatriglyceride levels. The methods comprise administering thepharmaceutical composition described in herein to a patient in need oflower ApoCIII levels, in an amount and for a duration sufficient todecrease the patient's serum or plasma ApoCIII levels. In anotherembodiment, the patient is at risk for cardiovascular heart disease.

In one embodiment, the pharmaceutical compositions described hereinminimize disruptive eructation and unpleasant fishy odors andaftertaste.

Another embodiment described herein is a pharmaceutical composition foradministration to a subject with hyperdyslipidemia or acardiovascular-related disease comprising a therapeutically effectiveamount of the fatty acids described herein, wherein the subject achievesa reduction of the annualized disease relapse rate relative to baselinewithout substantially experiencing one or more of disruptive eructationand unpleasant fishy odors and aftertaste. In one aspect the reductionmay be about 1%, about 2%, about 5%, about 10%, about 15%, about 20%,about 25%, about 30%, about 35%, about 45%, about 50%, or greater thanabout 50%.

Another embodiment described herein is a pharmaceutical composition ordosage form for treating, prophylaxis, or amelioration ofhyperdyslipidemia or a cardiovascular-related disease comprising aneffective amount of one or more fish oils (e.g., EPA, DHA or DPA or acombination thereof), wherein the composition exhibits an in vitrodissolution rate (% dissolution per minute) at pH 6.8, as describedherein.

Another embodiment described herein is a pharmaceutical composition fortreating, prophylaxis, or amelioration of hyperdyslipidemia includingbut not limited to cardiovascular-related diseases comprising one ormore fish oils (e.g., EPA, DHA or DPA or a combination thereof), whereinthe composition exhibits an in vitro dissolution rate comprising about10% to about 80% dissolution after about 5 minutes to about 480 minutesat pH 6.8, including each integer within the specified rages ofdissolution and time. In another aspect, the in vitro dissolution rateat pH 6.8 is about 50% after about 20 minutes.

In one embodiment, the pharmaceutical composition described herein issuitable for oral administration. In one aspect, the pharmaceuticalcomposition described herein is administered orally.

In one embodiment, the pharmaceutical composition described hereinprovides a relatively short T_(max) of EPA yet still maintains excellentstability of the encapsulated material. In one aspect, the compositionis provided in a dosage form containing a total amount of EPA whereinsubjects administered the dosage form exhibit a mean plasma EPA T_(max)ranging from about 5 hours to about 6 hours including all iterations ofintegers within the specified range. In another aspect, the compositionis provided in a dosage form containing a total amount of EPA, whereinsubjects administered the dosage form once daily exhibit a mean plasmaEPA T_(max) of at least 4 hours, at least 4.2 hours, at least 4.4 hours,at least 4.6 hours, at least 4.8 hours, at least 5 hours, at least 5.2hours, at least 5.4 hours, at least 5.6 hours, at least 5.8 hours, atleast 6 hours, at least 6.2 hours, at least 6.4 hours, or at least 6.6hours.

In one embodiment, the pharmaceutical composition described herein isprovided in a dosage form containing a total amount of EPA whereinsubjects administered the dosage form exhibit a mean plasma EPA C_(max)ranging from about 20 mg/L to about 500 mg/L including all iterations ofintegers within the specified range. In another aspect, the compositionis provided in a dosage form containing a total amount of EPA whereinsubjects administered the dosage form exhibit a mean plasma EPA C_(max)ranging from about 100 mg/L to about 250 mg/L including all iterationsof integers within the specified range. In another aspect, thecomposition is provided in a dosage form containing a total amount ofEPA wherein subjects administered the dosage form exhibit a mean plasmaEPA C_(max) of at least about 20 mg/L, at least about 40 mg/L, at leastabout 60 mg/L, at least about 80 mg/L, at least about 100 mg/L, at leastabout 150 mg/L, at least about 200 mg/L, or at least about 250 mg/L. Inone embodiment, the pharmaceutical composition is provided in a dosageform containing a total amount of EPA wherein subjects administered thedosage form exhibit a mean plasma EPA C_(max) of at least about 120 mg/Lto about 230 mg/L.

In one embodiment, the pharmaceutical composition described herein isprovided in a dosage form containing a total amount of EPA whereinsubjects administered the dosage form exhibit a mean plasma EPAAUC_(0→τ) ranging from about 300 h·mg/L to about 8500 h·mg/L includingall iterations of integers within the specified range. In one aspect,the composition is provided in a dosage form containing a total amountof EPA wherein subjects administered the dosage form exhibit a meanplasma EPA AUC_(0→τ) ranging from about 1800 h·mg/L to about 3000 h·mg/Lincluding all iterations of integers within the specified range. Inanother aspect, the composition is provided in a dosage form containinga total amount of EPA wherein subjects administered the dosage formexhibit a mean plasma EPA AUC_(0→τ) ranging from about 2500 h·mg/L toabout 5000 h·mg/L including all iterations of integers within thespecified range. In another aspect, the composition is provided in adosage form containing a total amount of EPA wherein subjectsadministered the dosage form exhibit a mean plasma EPA AUC_(0→τ) rangingfrom about 5000 h·mg/L to about 8500 h·mg/L including all iterations ofintegers within the specified range. In another aspect, the compositionis provided in a dosage form containing a total amount of EPA whereinsubjects administered the dosage form exhibit a mean plasma EPAAUC_(0→τ) of at least about 500 h·mg/L, at least about 600 h·mg/L, atleast about 700 h·mg/L, at least about 800 h·mg/L, at least about 900h·mg/L, at least about 1000 h·mg/L, at least about 1250 h·mg/L, at leastabout 1500 h·mg/L, at least about 1750 h·mg/L, at least about 2000h·mg/L, at least about 2250 h·mg/L, at least about 2500 h·mg/L, at leastabout 2750 h·mg/L, or at least about 3000 h·mg/L. In one embodiment, thepharmaceutical composition described herein is provided in a dosage formcontaining a total amount of EPA wherein subjects administered thedosage form exhibit a mean plasma EPA AUC_(0→τ) ranging from about 1850h·mg/L to about 2900 h·mg/L including all iterations of integers withinthe specified range.

In one embodiment, the pharmaceutical composition described herein isprovided in a dosage form containing a total amount of EPA whereinsubjects administered the dosage form exhibit a mean plasma EPAAUC_(0→∞) ranging from about 1000 h·mg/L to about 8500 h·mg/L includingall iterations of integers within the specified range. In one aspect,the composition is provided in a dosage form containing a total amountof EPA wherein subjects administered the dosage form exhibit a meanplasma EPA AUC_(0→∞) ranging from about 1800 h·mg/L to about 3000 h·mg/Lincluding all iterations of integers within the specified range. Inanother aspect, the composition is provided in a dosage form containinga total amount of EPA wherein subjects administered the dosage formexhibit a mean plasma EPA AUC_(0→∞) ranging from about 2000 h·mg/L toabout 3000 h·mg/L including all iterations of integers within thespecified range. In another aspect, the composition is provided in adosage form containing a total amount of EPA wherein subjectsadministered the dosage form exhibit a mean plasma EPA AUC_(0→τ) of atleast about 2000 h·mg/L, at least about 2050 h·mg/L, at least about 2100h·mg/L, at least about 2200 h·mg/L, at least about 2300 h·mg/L, at leastabout 2400 h·mg/L, at least about 2500 h·mg/L, at least about 2600h·mg/L, at least about 2700 h·mg/L, at least about 2800 h·mg/L, at leastabout 2900 h·mg/L, or at least about 3000 h·mg/L. In one embodiment, thepharmaceutical composition described herein is provided in a dosage formcontaining a total amount of EPA wherein subjects administered thedosage form exhibit a mean plasma EPA AUC_(0→∞) ranging from about 2050h·mg/L to about 3000 h·mg/L including all iterations of integers withinthe specified range.

In one embodiment, the pharmaceutical composition described herein, whenadministered to a subject, provides one or more of the followingpharmacokinetic parameters: (a) a mean plasma EPA T_(max) of about 5hours to about 6 hours; (b) a mean plasma EPA C_(max) of about 110 mg/Lto about 248 mg/L; (c) a mean plasma EPA AUC_(0→τ) of about 1650 h·mg/Lto about 3146 h·mg/L; (d) a mean plasma EPA AUC_(0→∞) of about 1836·mg/Lto about 3300 mg/L; (e) a mean EPA half-life (t½) of about 33 hours toabout 47 hours; or (f) a mean EPA overall elimination rate constant(k_(e1)) of about 0.016 h⁻¹ to about 0.023 h⁻¹.

In one embodiment, the pharmaceutical composition described herein isprovided in a dosage form containing a total amount of EPA whereinsubjects administered the dosage form exhibit a bioavailability ofgreater than about 50% to about 2000% as compared to the bioavailabilityof a reference drug comprising EPA ethyl ester in a soft gelatincapsule. In one embodiment, the pharmaceutical composition describedherein has a bioavailability of greater than about 50% to about 100% ascompared to the bioavailability of a reference drug comprising EPA ethylester in a soft gelatin capsule when administered to a subject in thefed state or with a low-fat meal. In one embodiment, the pharmaceuticalcomposition described herein has a bioavailability of greater than about100% to about 200% as compared to the bioavailability of a referencedrug comprising EPA ethyl ester in a soft gelatin capsule whenadministered to a subject in the fasted state or with a low-fat meal.

In another embodiment described herein, the pharmaceutical compositiondescribed herein provides enhanced bioavailability of EPA free fattyacid independent of the presence of food in a subject's gastrointestinaltract. Without being bound to any theory, it is believed that deliveryof the EPA free fatty acid to the lower gastrointestinal tract(intestine) reduces the food-effect and improves absorption and uptakeof the fatty acid into the bloodstream.

In another embodiment described herein, the pharmaceutical compositiondescribed herein comprises highly pure EPA free fatty acid whenadministered to a subject in need thereof does not induce a substantialincrease in the subject's LDL level relative to baseline.

It will be readily apparent to one of ordinary skill in the relevantarts that suitable modifications and adaptations to the compositions,methods, and applications described herein can be made without departingfrom the scope of any embodiments or aspects thereof. The compositionsand methods provided are exemplary and are not intended to limit thescope of any of the specified embodiments. All of the variousembodiments, aspects, and options disclosed herein can be combined inany and all variations or iterations. The scope of the compositions,formulations, methods, and processes described herein include all actualor potential combinations of embodiments, aspects, options, examples,and preferences herein described. The ratios of the mass of anycomponent of any of the formulations disclosed herein to the mass of anyother component in the formulation or to the total mass of the othercomponents in the formulation are hereby disclosed as if they wereexpressly disclosed. All patents and publications cited herein areincorporated by reference herein for the specific teachings thereof.

EXAMPLES Example 1

Examples of gel mass compositions useful for producing enteric softcapsules described herein comprising the pharmaceutical compositionsdescribed herein are shown below in Table 3. Composition components areset forth by weight percentage of the total weight of the gel masscomposition.

TABLE 3 Exemplary Enteric Soft Capsule Gel Composition Weight Percentage(%) Ingredient EX 1 EX 2 EX 3 EX 4 EX 5 EX 6 Gelatin 29.2 33.2 0 39.5 3327.8 Plasticizer 18 16 10.4 20 15 17.8 Pectin 0 3.3 0 0 2.4 0poly(methacylic acid-co- 11.2 0 9.7 10 0 0 methyl methacrylate) 1:1(L100) poly(methacylic acid-co- 0 0 0 0 0 10.8 ethyl acrylate) 1:1(L100-55) Ammonium hydroxide 1.7 0 1.2 1.5 0 Sodium hydroxide 0 0 0 0 03.6 Triethyl citrate 1.3 0 0 0 0 0 Calcium chloride 0 0 0 0 0.004 0Hydroxypropyl starch 0 0 9.2 0 0 0 phosphate Water 38.7 47.5 63 19 49.140 TOTAL 100 100 100 100 100 100

Example 2

In one embodiment, the enteric soft capsule shell has the composition ofTable 4, including all possible iterations of the specified ranges thatprovide 100% for the total weight percentage, including or excluding theoptional, excipients, opacifiers, colorants, and flavorings.

TABLE 4 Exemplary Enteric Soft Capsule Shell Composition ExemplaryComposition Component Component Range (%) Film-forming polymer Gelatin20-36 Enteric, acid-insoluble Methacrylic Acid  8-20 polymer CopolymerPlasticizer Glycerol, Triethyl citrate 10-22 Alkali-neutralizing agentsNH₄OH (30%), NaOH 1-5 Solvent Water 20-40 Opacifier Titanium Dioxide  1-7.5 Colorant (optional) Various 0.05-1   Flavoring (optional)Various 0.05-2   Excipients (optional) Various 1-5

In one embodiment described herein, the enteric soft capsule shell hasthe exemplary composition shown in Table 5.

TABLE 5 Exemplary Enteric Soft Capsule Shell Composition ComponentPercent Weight (%) Gelatin 29.2 Methacrylic Acid Copolymer (EUDRAGIT ® L100) 11.2 Glycerol 18.0 Triethyl citrate 1.3 Ammonium hydroxide 1.7Titanium dioxide 1.5 Water 37.1 TOTAL 100% Final pH 8.5-9.0 Totalpolymer % weight (gelatin + enteric) 40.4 Gelatin % weight of totalpolymer (gelatin + enteric) 72.4 Enteric % weight of total polymer(gelatin + enteric) 27.6 Ratio of Enteric to Gelatin 11.2:29.2 (0.38)Total plasticizer % weight (glycerol + triethyl citrate) 19.3 Ratio oftotal plasticizer to total polymer 19.3:40.4 (0.48) Ratio totalplasticizer to gelatin 19.3:29.2 (0.66) Ratio total plasticizer toenteric 19.3:11.2 (1.73) Water content in dried enteric soft capsule: 8-15

Example 3

In one embodiment described herein, the pharmaceutical compositiondescribed herein has the exemplary composition shown in Table 6.

TABLE 6 Exemplary Pharmaceutical Composition Component Percent Weight(%) Enteric Soft Capsule Shell Gelatin 29.2 Methacrylic Acid Copolymer11.2 (EUDRAGIT ® L 100) Glycerol 18.0 Triethyl citrate 1.3 Ammoniumhydroxide 1.7 Water 38.6 Total 100% API Eicosapentaenoic acid (EPA; freeacid) 92-98%; 1000 mg nominally ~94% Other omega fatty acids, oils,vitamins, ~ excipients: 4-8%; (Less than 1% DHA)

Example 4

A single-center, randomized, open-label, single-dose, four-period, twosequence crossover clinical study with 32 healthy volunteers wasperformed to evaluate the bioavailability of the “Test” pharmaceuticalcomposition comprising 4000 mg (4×1000 mg) of ˜94% eicosapentaenoicacid, free fatty acid (EPA-FFA) in an enteric soft gel capsule (seeTable 6, above) as compared to a Reference Listed Drug (RLD) comprising˜4000 mg (4×960 mg) eicosapentaenoic acid ethyl ester (EPA-EE) in atypical soft gel capsule under fasted and high-fat dosing conditions.

The study was a 47-day trial that included a 21-day screening period anda 26-day treatment period. This study assessed the relativebioavailability of EPA free fatty acid as compared to an EPA ethyl esterformulation and to assess the safety and tolerability of a single 4-gramdose of EPA administered under fasting (i.e., low fat) and fed (i.e.,high-fat) dosing conditions. See Table 7.

TABLE 7 Randomized Crossover Clinical Study Day 1 Day 1 Day 1 Day 1Period 1 Period 2 Period 3 Period 4 Fasting/Low Fat Diet Fasting/Low FatDiet Fed/High Fat Diet Fed/High Fat Diet Test: 16 Sub. (TL) → RLD: 16Sub. (RL) → Test: 16 Sub. (TH) → RLD: 16 Sub. (RH) 4 g EPA-FFA 4 gEPA-EE 4 g EPA-FFA 4 g EPA-EE RLD: 16 Sub. (RL) → Test 16 Sub. (TL) →RLD: 16 Sub. (RH) → Test 16 Sub. (TH) 4 g EPA-EE 4 g EPA-FFA 4 g EPA-FFA4 g EPA-EE

Thirty-two (32) healthy subjects (19 male; 59.4%; 13 female; 40.6%) wereenrolled and randomized to treatment; 30 subjects (93.8%) completed thestudy as planned; 32 subjects (100.0%) were included in the SafetyPopulation and 32 (100%) were included in the Pharmacokinetic (PK)Populations. Two (2) subjects discontinued participation in the study.

Subjects were representative of a healthy adult male and femalepopulation, ranging from 19 to 52 years of age. Overall mean (SD) agewas 35.7 (10.32) years and mean (SD) BMI was 24.88 (2.376) kg/m². Racialcomposition was 12 (37.5%) black or African American and 20 (62.5%)white. Ethnicity was 19 (59.4%) Hispanic or Latino and 13 (40.6%)Non-Hispanic and Non-Latino.

The study consisted of a screening visit within 21 days before admissionfor Period 1, and admission to the unit at −49 hour pre-dose in eachperiod, followed by four periods of single-dose administration of thestudy drugs. There was a minimum of −7 days washout between eachsingle-dose administration. Upon admission, on Day −3 of each period,subjects were given meals that followed the Therapeutic LifestyleChanges (TLC) diet and that contained limited EPA (e.g., EPA-limiteddiet). See, e.g., Your Guide to Lowering Cholesterol With TherapeuticLifestyle Changes (TLC), U.S. Department of Health and Human Services,National Institutes of Health, National Heart, Lung, and BloodInstitute, NIH Publication ID: 06-5235, December 2005, which isincorporated by reference herein in its entirety for such teachings.Approximately 12 hours prior to dosing in all four periods, the subjectsconsumed a low fat dinner (9 g fat; 900 kcal).

The low fat meals for Periods 1 and 2 were as follows:

-   -   Day 1: (the day of dosing): no breakfast—fasting administration        of drug (0 g fat; 0 kcal); no-fat lunch (0 g fat; 600 kcal);        low-fat dinner (9 g fat; 900 kcal); no-fat evening snack.    -   Day 2: Meals followed the EPA-limited diet.

The high-fat meals for Periods 3 and 4 were as follows:

-   -   Day 1: high-fat breakfast, 45 minutes before dosing (20 g fat;        600 kcal); high-fat lunch (30 g fat; 900 kcal); high-fat dinner        (30 g fat; 900 kcal); evening snack.    -   Day 2: Meals followed the EPA-limited diet.

Subjects resumed the TLC diet after the last samples at 48 hourspost-dose during the outpatient portion of all periods. Subjects adheredto the TLC diet during the outpatient portions of the study and betweenTreatment Periods.

During each treatment period, subjects received one of the followingopen label treatments:

-   -   Test Formulation (T): a single dose of EPA free fatty acid, 4×1        g capsules    -   Reference Formulation (R): a single dose of EPA ethyl ester, 4×1        g capsules.

A total of 20 blood samples were collected from the subjects at timeintervals of −24, −16, −8, −0.75 (time=0) hours pre-dosing and at 1, 2,3, 4, 5, 6, 7, 8, 9, 10, 12, 14, 16, 24, 32, and 48 hours post dosingand were analyzed for the plasma bioavailability of the fatty acid. Whenmeal time coincided with the blood sample time, the blood samples werecollected prior to the meal being consumed.

The following PK parameters were determined using plasma concentrationsof Total EPA and Free EPA (non-esterified EPA), as permitted by thedata:

-   -   C_(max): Maximum plasma concentration observed.    -   T_(max): Time to maximum concentration observed.    -   AUC_(0→τ): Area under the plasma concentration-time curve from        time 0 to the last quantifiable time point (Cτ).    -   AUC_(0→∞): Area under the plasma concentration-time curve from        time 0 to infinity, calculated as AUC_(0→τ)+Cτ/λz.

The study's primary endpoints were the 90% Confidence Intervals on theratio of the geometric means of the single-dose pharmacokineticparameters AUC_(0→τ), AUC_(0→∞), and C_(max) between the followingtreatment comparisons:

-   -   TL versus RL: Fasted administration of Test and Reference        followed by low-fat diet.    -   TH versus RH: Fed administration of Test and Reference followed        by high-fat diet.    -   TH versus TL: Food effect on Test.    -   RH versus RL: Food effect on Reference.    -   (TH/TL) versus (RH/RL): Ratio between food effect on the Test        and food effect on the Reference.

The parameters AUC_(0→τ), AUC_(0→∞), and C_(max) were log transformedprior to analysis and were analyzed using a mixed model. Treatments werecompared using an analysis of variance (ANOVA) model on thelog-transformed data. The model includes sequence, period, and treatmentas fixed effects and subject nested within sequence as a random effect.For AUCs and C_(max), point estimates (least square means) for treatmentdifferences as well as the 90% Confidence Interval (CI) were calculatedon log scales and then exponentiated to provide estimates of, andconfidence intervals for, the geometric mean ratios. The residualvariance from the mixed model was used to calculate the 90% CI for thedifference between the Test and Reference treatment. Pharmacokineticdata and parameters are shown in Tables 8-15. The averaged plasma EPAfree fatty acid (Test)/EPA ethyl ester (RLD) concentrations as afunction of time are shown in FIG. 6.

TABLE 8 Mean Baseline-Adjusted Plasma Total EPA PharmacokineticParameters by Treatment TL (Test) RL (RLD) TH (Test) RH (RLD) 4 gEPA-FFA 4 g EPA-EE 4 g EPA-FFA 4 g EPA-EE Parameter Statistic Low FatDiet Low Fat Diet High Fat Diet High Fat Diet AUC_(0→τ) n 32 31 30 32(hr · μg/mL) Mean (SD) 1841 (739.0) 126.7 (92.68) 2864 (1094) 1781(955.9) AUC_(0→∞) n 2 2 NA 1 (hr · μg/mL) Mean (SD) 2044 (1105) 27.64(19.94) NA 3063 (NA) C_(max) (μg/mL) n 32 31 30 32 Mean (SD) 122.1(62.55) 7.507 (8.554) 225.6 (99.88) 136.6 (77.96) T_(max) (hr) n 32 3130 32 Median 6.00 9.00 5.00 5.00 Min, Max 4.00, 10.00 4.00, 48.00 3.00,12.00 4.00, 12.00 t½ (hr) n 28 4 29 31 Mean (SD) 43.34 (19.13) 7.80(5.44) 36.88 (10.23) 37.59 (9.96) k_(el) (1/hr) n 28 4 29 31 Mean (SD)0.0190 (0.0083) 0.1639 (0.1721) 0.0202 (0.0055) 0.0198 (0.0057) Median0.0178 0.0946 0.0199 0.0192 Min, Max 0.0067, 0.0435 0.0465, 0.41970.0106, 0.0364 0.0118, 0.0351 TL: Test Fasting/Low-Fat Diet RL:Reference Fasting/Low-Fat Diet TH: Test High-Fat Diet RH: ReferenceHigh-Fat Diet n = number of subjects

TABLE 9 Mean Baseline-Adjusted Plasma Free EPA PharmacokineticParameters by Treatment TL Test RL RLD TH Test RH RLD 4 g EPA-FFA 4 gEPA-EE 4 g EPA-FFA 4 g EPA-EE Parameter Statistic Low Fat Diet Low FatDiet High Fat Diet High Fat Diet AUC_(0→τ) n 32 32 30 32 (hr · μg/mL)Mean (SD) 8.810 (3.651) 2.581 (1.094) 12.96 (3.149) 7.846 (2.707)AUC_(0→∞) n NA NA 1 NA (hr · μg/mL) Mean (SD) NA NA 12.58 (NA) NAC_(max) (μg/mL) n 32 32 30 32 Mean (SD) 1.132 (0.6918) 0.1271 (0.0570)1.894 (1.074) 0.9911 (0.4644) T_(max) (hr) n 32 32 30 32 Median 5.004.00 6.00 6.00 Min, Max 4.00, 10.00 2.00, 48.00 4.00, 12.00 3.00, 10.00t½ (hr) n 1 1 1 NA Mean (SD) 26.27 (NA) 117.83 (NA) 17.79 (NA) NA (NA)k_(el) (1/hr) n 1 1 1 NA Mean (SD) 0.0264 (NA) 0.0059 (NA) 0.0390 (NA)NA (NA) Median 0.0264 0.0059 0.0390 NA Min, Max 0.0264, 0.0264 0.0059,0.0059 0.0390, 0.0390 NA TL: Test Fasting/Low-Fat Diet RL: ReferenceFasting/Low-Fat Diet TH: Test High-Fat Diet RH: Reference High-Fat Dietn = number of subjects

TABLE 10 Bioavailability of Total and Free EPA Between EPA Free FattyAcid (Fasting/Low-Fat Diet) and EPA Ethyl Ester (Fasting/Low-Fat Diet)Geometric Least Square Means TL/RL 90% CI ISCV Analyte n Param. TL RLRatio (%) (LCL-UCL) (%) Total EPA (BA) 30 C_(max) 114.4 5.220 2191.79(1786.06-2689.68) 49.25 AUC_(0→τ) 1796 88.78 2022.93 (1564.59-2615.53)63.87 Free EPA (BA) 31 C_(max) 0.9785 0.1144 855.46  (708.56-1032.83)45.80 AUC_(0→τ) 8.543 2.109 405.12 (330.77-496.19) 49.67 Total EPA (UN)31 C_(max) 126.0 18.00 699.94 (616.62-794.53) 30.00 AUC_(0→τ) 2346 704.1333.26 (306.62-362.20) 19.47 Free EPA (UN) 31 C_(max) 1.010 0.1409716.34 (598.59-857.24) 43.45 AUC_(0→τ) 9.811 3.205 306.13(248.11-377.70) 51.69 BA: baseline adjusted UN: uncorrected n = numberof subjects TL: Test Fasting/Low-Fat Diet RL: Reference Fasting Low-FatDiet CI = 90% confidence interval, LCL = lower confidence limit, UCL =upper confidence limit ISCV = intra-subject coefficient of variation

TABLE 11 Bioavailability of Total and Free EPA Between EPA Free FattyAcid (High-Fat Diet) and EPA Ethyl Ester (High Fat Diet) Geometric LeastSquare Means TH/RH 90% CI ISCV Analyte n Param. TH RH Ratio (%)(LCL-UCL) (%) Total EPA (BA) 30 C_(max) 206.6 110.6 186.80(149.23-233.82) 54.51 AUC_(0→τ) 2702 1554 173.86 (154.21-196.01) 27.76Free EPA (BA) 30 C_(max) 1.662 0.8828 188.23 (153.20-231.28) 49.46AUC_(0→τ) 12.64 7.353 171.98 (152.05-194.52) 28.53 Total EPA (UN) 30C_(max) 220.6 128.8 171.22 (140.98-207.94) 46.38 AUC_(0→τ) 3347 2327143.82 (133.28-155.18) 17.40 Free EPA (UN) 30 C_(max) 1.699 0.9299182.68 (150.05-222.41) 47.04 AUC_(0→τ) 14.31 9.342 153.19(139.17-168.63) 22.07 BA: baseline adjusted UN: uncorrected n = numberof subjects TH: Test High-Fat Diet RL: Reference High-Fat Diet CI = 90%confidence interval, LCL = lower confidence limit, UCL = upperconfidence limit ISCV = intra-subject coefficient of variation

TABLE 12 Food Effect of Total and Free EPA Between EPA Free Fatty Acid(Fed/High-Fat Diet) and EPA Free Fatty Acid (Fasting/Low-Fat Diet)Geometric Least Square Means TH/TL 90% CI ISCV Analyte n Param. TH TLRatio (%) (LCL-UCL) (%) Total EPA (BA) 29 C_(max) 207.7 116.7 177.92(146.23-216.49) 46.99 AUC_(0→τ) 2761 1817 151.92 (131.17-175.95) 34.39Free EPA (BA) 29 C_(max) 1.659 1.006 164.98 (128.36-212.05) 62.15AUC_(0→τ) 12.71 8.744 145.41 (127.34-166.04) 30.91 Total EPA (UN) 29C_(max) 221.6 129.3 171.47 (142.79-205.90) 43.54 AUC_(0→τ) 3405 2380143.10 (125.64-163.00) 30.29 Free EPA (UN) 29 C_(max) 1.696 1.036 163.73(128.00-209.45) 60.77 AUC_(0→τ) 14.37 9.999 143.68 (126.26-163.51) 30.08BA: baseline adjusted UN: uncorrected n = number of subjects TH: TestHigh-Fat Diet TL: Test Fasting Low-Fat Diet CI = 90% confidenceinterval, LCL = lower confidence limit, UCL = upper confidence limitISCV = intra-subject coefficient of variation

TABLE 13 Food Effect of Total and Free EPA Between EPA Ethyl Ester(Fed/High-Fat Diet) and EPA Ethyl Ester (Fasting/Low-Fat Diet) GeometricLeast Square Means RH/TL 90% CI ISCV Analyte n Param. RH RL Ratio (%)(LCL-UCL) (%) Total EPA (BA) 31 C_(max) 118.1 5.615 2104.04(1585.56-2792.07) 74.82 AUC_(0→τ) 1626 89.93 1807.47 (1313.56-2487.10)87.23 Free EPA (BA) 32 C_(max) 0.8843 0.1164 759.79 (625.53-922.86)49.22 AUC_(0→τ) 7.366 2.188 336.70 (262.01-432.67) 65.93 Total EPA (UN)32 C_(max) 132.3 18.72 707.01 (577.24-865.96) 51.59 AUC_(0→τ) 2359 699.0337.43 (290.15-392.40) 37.37 Free EPA (UN) 32 C_(max) 0.9306 0.1430650.77 (536.97-788.67) 48.59 AUC_(0→τ) 9.328 3.302 282.51(216.62-368.45) 70.63 BA: baseline adjusted UN: uncorrected n = numberof subjects RH: Reference High-Fat Diet RL: Reference Fasting Low-FatDiet CI = 90% confidence interval, LCL = lower confidence limit, UCL =upper confidence limit ISCV = intra-subject coefficient of variation

TABLE 14 Bioavailability of Total and Free EPA Between EPA Free FattyAcid (Fed/High Fat Diet)/(Fasting/Low-Fat Diet) and EPA Ethyl Ester(Fed/High Fat Diet)/(Fasting/Low-Fat Diet) Geometric Least Square MeansTH/TL RH/RL (TH/TL)/(RH/RL) 90% CI ISCV Analyte Param. n = 30 n = 30Ratio (%) (LCL-UCL) (%) Total EPA (BA) C_(max) 2.203 21.04 10.47 (7.08-15.49) 109.82 AUC_(0→τ) 1.904 18.07 10.53  (6.50-17.07) 160.39Free EPA (BA) C_(max) 2.569 7.598 33.81 (25.57-44.72) 63.89 AUC_(0→τ)1.813 3.512 51.61 (36.61-72.76) 88.92 Total EPA (UN) C_(max) 1.947 7.07027.54 (21.37-35.49) 64.04 AUC_(0→τ) 1.618 3.374 47.95 (38.09-60.35)58.45 Free EPA (UN) C_(max) 2.513 6.508 38.62 (29.41-50.72) 62.02AUC_(0→τ) 1.720 2.825 60.87 (43.52-85.15) 88.42 BA: baseline adjustedUN: uncorrected n = number of subjects TH: Test High-Fat Diet TL: TestFasting Low-Fat Diet RH: Reference High-Fat Diet RL: Reference FastingLow-Fat Diet TH/TL: Ratio of Test High-Fat Diet to Low-Fat Diet RH/RL:Ratio of Reference High-Fat Diet to Low-Fat Diet CI = 90% confidenceinterval, LCL = lower confidence limit, UCL = upper confidence limitISCV = intra-subject coefficient of variation

TABLE 15 Summary Pharmacokinetic Parameters (Total EPA) Ratio LowerUpper Treatment Dependent Ref. Test % Ref 90% CI 90% CI ReferenceLn(C_(max)) RL RH 2029.11 1525.85 2698.36 Ln(AUC_(0→τ)) RL RH 1757.261279.08 2414.22 Test Ln(C_(max)) TL TH 182.14 150.38 220.61Ln(AUC_(0→τ)) TL TH 154.20 133.65 177.91 TH: Test High-Fat Diet TL: TestFasting Low-Fat Diet RH: Reference High-Fat Diet RL: Reference FastingLow-Fat Diet

TABLE 16 Summary Pharmacokinetic Parameters as a Function of Food (TotalEPA) Ratio Lower Upper Conditions Dependent Ref. Test % Ref 90% CI 90%CI Fasted/Low Ln(C_(max)) RL TL 2178.42 1779.55 2666.70 Fat DietLn(AUC_(0→τ)) RL TL 2015.75 1563.65 2598.57 Fed/High Ln(C_(max)) RH TH182.22 146.17 227.16 Fat Diet Ln(AUC_(0→τ)) RH TH 172.55 153.26 194.26TH: Test High-Fat Diet TL: Test Fasting Low-Fat Diet RH: ReferenceHigh-Fat Diet RL: Reference Fasting Low-Fat Diet

These data show that EPA plasma concentrations and total exposures werehigher for both the Test and Reference when administered in thefed/high-fat diet state. The EPA exposure for the Test (EPA free fattyacid) is much higher than the Reference (EPA ethyl ester in a soft gelcapsule) under fasting conditions/low fat diet; the Reference exposureis extremely low. Food has a much smaller effect on the Test as comparedto the Reference.

Surprisingly, under fasted/low fat conditions, the bioavailability ofthe Test pharmaceutical composition was ˜2000% greater than the RLD.Under fed (high-fat) conditions, the bioavailability the Testpharmaceutical composition was ˜70-80% higher than the RLD.

This study showed that food and the fat content of food has asignificant effect on the bioavailability of the RLD, whereas food has amuch smaller effect on the bioavailability of the Test EPA free fattyacid enteric soft capsules. The absorption of EPA free fatty acid in theintestine diminishes the effect of food on absorption. Accordingly, theTest pharmaceutical composition, as described herein, does not requirehigh fat meals to facilitate bioavailability of the EPA free fatty acidactive pharmaceutical ingredient. The high bioavailability may be usedto reduce the dosage quantity (e.g., 1 g instead of 4 g) required toachieve a therapeutic effect and may lead to better patient compliance.

These findings are advantageous for the treatment of patients withelevated triglyceride levels because these patients often have acontrolled, low-fat diet as part of their therapy and thus they shouldnot consume high fat meals. In addition, because the Test pharmaceuticalcomposition does not contain docosahexaenoic acid (DHA), no increases inlow-density lipoprotein levels (LDL) are expected in patients receivingthis composition. This may provide a valuable therapeutic option fortreating patients with very high triglycerides (e.g., severehypertriglyceridemia; TG ≧500 mg/dL) and those with high triglycerides(e.g., 200-500 mg/dL). Further, the controlled release enteric softcapsules reduce the incidence of “fishy burps”—eructation with fishyaftertaste or odor—because this pharmaceutical composition does notdissolve and release the EPA oil in the stomach.

What is claimed is:
 1. An oral pharmaceutical composition comprising anenteric soft capsule shell consisting essentially of: about 25% to about40% by weight of gelatin; about 9% to about 11% by weight of an entericpolymer; about 10% to about 22% by weight of a plasticizer; about 1% toabout 4% by weight of an alkali neutralizing agent; and about 19% toabout 65% by weight of a solvent; wherein the enteric polymer andgelatin is in a mixture in a 1:2.6 weight ratio of the enteric polymerto the gelatin; and wherein the shell encapsulates a matrix fillcomprising at least 94% by weight eicosapentaenoic free fatty acid (EPA)and less than 1% by weight docosahexaenoic acid (DHA); wherein uponadministration to a subject, an EPA C_(max) ratio of a high-fat fedsubject and a fasted subject fed a low-fat diet is less than 3:1.
 2. Thecomposition of claim 1, wherein the fill comprises about 250 mg to about1000 mg of EPA.
 3. The composition of claim 1, wherein uponadministration to a subject, the subject experiences a minimal incidenceof one or more of eructation, abdominal discomfort, nausea, diarrhea,fishy aftertaste, or fishy odor.
 4. The composition of claim 1, whereinthe capsule shell and matrix fill composition are stable for at least 1year at 25° C., 60% relative humidity.
 5. The composition of claim 1,wherein the capsule shell does not dissolve in simulated gastric fluid(pH 1.2) for at least 1 hour, and begins dissolution in simulatedintestinal fluid (pH 6.8) within about 15 minutes.
 6. The composition ofclaim 1, wherein upon administration to a subject the compositionprovides a mean plasma EPA C_(max) of about 122 mg/L to about 226 mg/Land one or more of the following pharmacokinetic parameters: (a) a meanplasma EPA T_(max) of about 5 hours to about 6 hours; (b) a mean plasmaEPA AUC_(0→τ) of about 1840 h·mg/L to about 2860 h·mg/L; (c) a meanplasma EPA AUC_(0→∞) of about 2040·mg/L to about 3000 mg/L; (d) a meanEPA half-life (t½) of about 37 hours to about 43 hours; or (e) a meanEPA overall elimination rate constant (k_(e1)) of about 0.019 h⁻¹ toabout 0.020 h⁻¹.
 7. The composition of claim 1, wherein uponadministration to a subject the composition provides one or more of thefollowing pharmacokinetic parameters: (a) a mean plasma EPA T_(max) ofabout 6 hours under fasting/low fat conditions; (b) a mean plasma EPAC_(max) of about 122 mg/L under fasting/low fat conditions; (c) a meanplasma EPA AUC_(0→τ) of about 1840 h·mg/L under fasting/low fatconditions; (d) a mean plasma EPA AUC_(0→∞) of about 2040·mg/L underfasting/low fat conditions; (e) a mean EPA half-life (t½) of about 43hours under fasting/low fat conditions; or (f) a mean EPA overallelimination rate constant (k_(e1)) of about 0.019 h⁻¹ under fasting/lowfat conditions; or (g) a mean plasma EPA C_(max) of about 226 mg/L underfed/high fat conditions; (h) a mean plasma EPA AUC_(0→τ) of about 2860h·mg/L under fed/high fat conditions; (i) a mean plasma EPA AUC_(0→∞) ofabout 3000 mg/L under fed/high fat conditions.
 8. The composition ofclaim 1, wherein upon administration to a subject, the EPA has abioavailability of about 2000% of the bioavailability of a referencepharmaceutical composition comprising eicosapentaenoic ethyl ester underfasted/low fat conditions.
 9. The composition of claim 8, wherein thereference pharmaceutical composition comprises eicosapentaenoic ethylester in a soft gel capsule.
 10. The composition of claim 1, whereinupon administration to a subject the composition does not induce asubstantial increase in LDL level relative to baseline.
 11. Thecomposition of claim 1, wherein the composition is useful for treating,retarding the progression of, delaying the onset of, prophylaxis of,amelioration of, or reducing the symptoms of a cardiovascular-relateddisease, including but not limited to hyperlipidemia orhypertriglyceridemia.
 12. The composition of claim 1, wherein thecomposition is useful for treating, retarding the progression of,delaying the onset of, prophylaxis of, amelioration of, or reducing thesymptoms a medical condition comprising: cardiovascular-relateddiseases, hyperlipidemia, hypertriglyceridemia, hypertension,hypercholesterolemia, mixed dyslipidemia, sitosterolemia,atherosclerosis, or a combination thereof.
 13. The composition of claim1, wherein the enteric polymer is an acrylic and methacrylic acidcopolymer; the plasticizer is glycerol and triethyl citrate; the alkalineutralizing agent is selected from the group consisting of ammoniumhydroxide and sodium hydroxide; and the solvent is water.